Abstract
The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease. In this Review, we discuss the various components of the immune TME in breast cancer and therapies that target or impact the immune TME, as well as the complexity of host physiology.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J. Clin. 73, 17–48 (2023).
Arnold, M. et al. Current and future burden of breast cancer: global statistics for 2020 and 2040. Breast 66, 15–23 (2022).
Taylor, C. et al. Breast cancer mortality in 500 000 women with early invasive breast cancer diagnosed in England, 1993-2015: population based observational cohort study. BMJ 381, e074684 (2023).
Caswell-Jin, J. L. et al. Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review. JNCI Cancer Spectr. 2, pky062 (2018).
World Health Organization. Global health estimates 2020: deaths by cause, age, sex, by country and by region, 2000–2019 (WHO, 2020).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
Prat, A. et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 12, R68 (2010).
Cortes, J. et al. Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer. N. Engl. J. Med. 387, 217–226 (2022).
Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024).
Engels, E. A. Epidemiologic perspectives on immunosuppressed populations and the immunosurveillance and immunocontainment of cancer. Am. J. Transpl. 19, 3223–3232 (2019).
Schmid, P. et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N. Engl. J. Med. 386, 556–567 (2022). This phase III trial demonstrates that targeting PD1 with pembrolizumab combined with chemotherapy is more effective than chemotherapy alone in patients with early TNBC.
Schmid, P. et al. Pembrolizumab for early triple-negative breast cancer. N. Engl. J. Med. 382, 810–821 (2020).
Mittendorf, E. A. et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396, 1090–1100 (2020). This phase III trial demonstrates that targeting PDL1 with atezolizumab combined with chemotherapy is more effective than chemotherapy alone in patients with early TNBC.
Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615–620 (2020).
Loi, S. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J. Clin. Oncol. 31, 860–867 (2013).
Danenberg, E. et al. Breast tumor microenvironment structures are associated with genomic features and clinical outcome. Nat. Genet. 54, 660–669 (2022).
Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).
Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018). This study identifies four different subtypes of CAFs in breast cancer and elucidates their role in regulating T cell function by promoting immune suppression.
Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).
Savas, P. et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24, 986–993 (2018). This study uses scRNA-seq to identify T cells with a tissue-resident memory-like phenotype in breast cancer that are associated with an improved prognosis and suggests that these cells are key responders to ICB.
Salgado, R. et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 1, 448–454 (2015).
Loi, S. et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J. Clin. Oncol. 37, 559–569 (2019).
Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50 (2018).
Loi, S. et al. Association between biomarkers and clinical outcomes of pembrolizumab monotherapy in patients with metastatic triple-negative breast cancer: KEYNOTE-086 exploratory analysis. JCO Precis. Oncol. 7, e2200317 (2023).
Leon-Ferre, R. A. et al. Tumor-infiltrating lymphocytes in triple-negative breast cancer. JAMA 331, 1135–1144 (2024).
Salgado, R. et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann. Oncol. 26, 259–271 (2015).
Cardoso, F. et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1194–1220 (2019).
Burstein, H. J. et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019. Ann. Oncol. 30, 1541–1557 (2019).
Luen, S., Virassamy, B., Savas, P., Salgado, R. & Loi, S. The genomic landscape of breast cancer and its interaction with host immunity. Breast 29, 241–250 (2016).
Wagner, J. et al. A single-cell atlas of the tumor and immune ecosystem of human breast cancer. Cell 177, 1330–1345.e18 (2019). This study uses mass cytometry to analyse breast cancer samples to provide a comprehensive atlas of immune cell composition and phenotype in the TME and relationship with tumour cells.
Wu, S. Z. et al. A single-cell and spatially resolved atlas of human breast cancers. Nat. Genet. 53, 1334–1347 (2021).
Keren, L. et al. A structured tumor-immune microenvironment in triple negative breast cancer revealed by multiplexed ion beam imaging. Cell 174, 1373–1387.e19 (2018). This study uses multiplexed ion beam imaging by time-of-flight to analyse the immune microenvironment of TNBC samples, providing quantitative information and spatial information to reveal the organization of the TME.
Ali, H. R. et al. Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer. Nat. Cancer 1, 163–175 (2020).
Desmedt, C. et al. Immune infiltration in invasive lobular breast cancer. J. Natl Cancer Inst. 110, 768–776 (2018).
Cepek, K. L. et al. Adhesion between epithelial cells and T lymphocytes mediated by E-cadherin and the alpha E beta 7 integrin. Nature 372, 190–193 (1994).
Tietscher, S. et al. A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer. Nat. Commun. 14, 98 (2023).
Pal, B. et al. A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast. Embo j. 40, e107333 (2021). This study uses scRNA-seq to analyse the transcriptome of healthy breast, pre-neoplastic and breast cancer tissue, providing detailed resolution of the cellular diversity in healthy tissue to tumour.
Virassamy, B. et al. Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer. Cancer Cell 41, 585–601.e588 (2023).
Wang, Z. Q. et al. CD103 and intratumoral immune response in breast cancer. Clin. Cancer Res. 22, 6290–6297 (2016).
Lee, Y. J. et al. CD39+ tissue-resident memory CD8+ T cells with a clonal overlap across compartments mediate antitumor immunity in breast cancer. Sci. Immunol. 7, eabn8390 (2022).
Mackay, L. K. et al. Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention. J. Immunol. 194, 2059–2063 (2015).
Skon, C. N. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285–1293 (2013).
Allakhverdi, Z. et al. Expression of CD103 identifies human regulatory T-cell subsets. J. Allergy Clin. Immunol. 118, 1342–1349 (2006).
Shiow, L. R. et al. CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).
Gavil, N. V. et al. Chronic antigen in solid tumors drives a distinct program of T cell residence. Sci. Immunol. 8, eadd5976 (2023).
Corgnac, S. et al. CD103+CD8+ TRM cells accumulate in tumors of anti-PD-1-responder lung cancer patients and are tumor-reactive lymphocytes enriched with Tc17. Cell Rep. Med. 1, 100127 (2020).
Luoma, A. M. et al. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185, 2918–2935.e29 (2022).
Losurdo, A. et al. Single-cell profiling defines the prognostic benefit of CD39high tissue resident memory CD8+ T cells in luminal-like breast cancer. Commun. Biol. 4, 1117 (2021).
Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).
Canale, F. P. et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8+ T cells. Cancer Res. 78, 115–128 (2018).
Bossio, S. N. et al. CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade. Oncoimmunology 12, 2246319 (2023).
Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011).
Raghu, D., Xue, H. H. & Mielke, L. A. Control of lymphocyte fate, infection, and tumor immunity by TCF-1. Trends Immunol. 40, 1149–1162 (2019).
Johnson, J. L. et al. Lineage-determining transcription factor TCF-1 initiates the epigenetic identity of T cells. Immunity 48, 243–257.e10 (2018).
Wang, X. Q. et al. Spatial predictors of immunotherapy response in triple-negative breast cancer. Nature 621, 868–876 (2023).
Bassez, A. et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat. Med. 27, 820–832 (2021). This study identifies genes associated with T cell expansion post-treatment through single-cell profiling and T cell receptor sequencing of biopsies collected pre-anti-PD1 treatment and after anti-PD1 treatment.
Salgado, R. et al. How current assay approval policies are leading to unintended imprecision medicine. Lancet Oncol. 21, 1399–1401 (2020).
Qin, Y. et al. Tumor-infiltrating B cells as a favorable prognostic biomarker in breast cancer: a systematic review and meta-analysis. Cancer Cell Int. 21, 310 (2021).
Garaud, S. et al. Tumor infiltrating B-cells signal functional humoral immune responses in breast cancer. JCI Insight 5, e129641 (2019).
Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).
Thacker, G. et al. Immature natural killer cells promote progression of triple-negative breast cancer. Sci. Transl. Med. 15, eabl4414 (2023).
Wang, Y. et al. Tissue-resident macrophages promote extracellular matrix homeostasis in the mammary gland stroma of nulliparous mice. eLife 9, e57438 (2020).
Dawson, C. A. et al. Tissue-resident ductal macrophages survey the mammary epithelium and facilitate tissue remodelling. Nat. Cell Biol. 22, 546–558 (2020).
Plaks, V. et al. Adaptive immune regulation of mammary postnatal organogenesis. Dev. Cell 34, 493–504 (2015).
Azizi, E. et al. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174, 1293–1308.e36 (2018). This study concludes, through scRNA-seq and T cell receptor sequencing profiling of immune cells from breast tumours and matched, blood, lymph node and normal breast tissue, that T cells exist in a state of continuous activation and that macrophages do not exist in distinct states of polarization.
Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602.e10 (2019).
Onkar, S. et al. Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment. Nat. Cancer 4, 516–534 (2023).
Jaitin, D. A. et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 178, 686–698.e14 (2019).
Nalio Ramos, R. et al. Tissue-resident FOLR2+ macrophages associate with CD8+ T cell infiltration in human breast cancer. Cell 185, 1189–1207.e25 (2022). This study identifies FOLR2+ tissue-resident macrophages in breast cancer which interact with and prime T cells and are associated with improved patient survival.
Cansever, D. et al. Lactation-associated macrophages exist in murine mammary tissue and human milk. Nat. Immunol. 24, 1098–1109 (2023).
Molgora, M. et al. TREM2 modulation remodels the tumor myeloid landscape enhancing anti-PD-1 immunotherapy. Cell 182, 886–900.e17 (2020). This study finds TREM2 expression to be inversely correlated with overall survival in patients with TNBC and identifies TREM2 as a potential target on tumour-associated macrophages to improve responses to ICB.
Yofe, I. et al. Spatial and temporal mapping of breast cancer lung metastases identify TREM2 macrophages as regulators of the metastatic boundary. Cancer Discov. 13, 2610–2631 (2023).
Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13 (2017).
Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).
Bense, R. D. et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J. Natl Cancer Inst. 109, djw192 (2017).
Ali, H. R., Chlon, L., Pharoah, P. D., Markowetz, F. & Caldas, C. Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med. 13, e1002194 (2016).
Majorini, M. T., Colombo, M. P. & Lecis, D. Few, but efficient: the role of mast cells in breast cancer and other solid tumors. Cancer Res. 82, 1439–1447 (2022).
Reddy, S. M. et al. Poor response to neoadjuvant chemotherapy correlates with mast cell infiltration in inflammatory breast cancer. Cancer Immunol. Res. 7, 1025–1035 (2019).
Cords, L. et al. Cancer-associated fibroblast classification in single-cell and spatial proteomics data. Nat. Commun. 14, 4294 (2023).
Mayer, S. et al. The tumor microenvironment shows a hierarchy of cell-cell interactions dominated by fibroblasts. Nat. Commun. 14, 5810 (2023).
Wu, S. Z. et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 39, e104063 (2020).
Pelon, F. et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 11, 404 (2020).
Wu, Y. et al. FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts. Theranostics 12, 4564–4580 (2022).
Geldhof, V. et al. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat. Commun. 13, 5511 (2022).
Goveia, J. et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37, 21–36.e13 (2020).
Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).
Asrir, A. et al. Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell 40, 318–334.e19 (2022).
Martinet, L. et al. Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71, 5678–5687 (2011).
Chen, L. et al. Famitinib with camrelizumab and nab-paclitaxel for advanced immunomodulatory triple-negative breast cancer (FUTURE-C-Plus): an open-label, single-arm, phase II trial. Clin. Cancer Res. 28, 2807–2817 (2022).
Risom, T. et al. Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma. Cell 185, 299–310.e18 (2022). This study, using multiplexed ion beam imaging by time-of-flight to compare the TME of matched normal breast, DCIS and invasive breast cancer samples, suggests that DCIS with increased expression of E-cadherin and a continuous myoepithelium are at increased risk of recurrence.
Gil Del Alcazar, C. R. et al. Immune escape in breast cancer during in situ to invasive carcinoma transition. Cancer Discov. 7, 1098–1115 (2017).
Nachmanson, D. et al. The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ. NPJ Breast Cancer 8, 6 (2022).
Almekinders, M. M. et al. Comprehensive multiplexed immune profiling of the ductal carcinoma in situ immune microenvironment regarding subsequent ipsilateral invasive breast cancer risk. Br. J. Cancer 127, 1201–1213 (2022).
Strand, S. H. et al. Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: analysis of TBCRC 038 and RAHBT cohorts. Cancer Cell 40, 1521–1536.e27 (2022).
Szekely, B. et al. Immunological differences between primary and metastatic breast cancer. Ann. Oncol. 29, 2232–2239 (2018).
Cimino-Mathews, A. et al. PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum. Pathol. 47, 52–63 (2016).
Boman, C. et al. Discordance of PD-L1 status between primary and metastatic breast cancer: a systematic review and meta-analysis. Cancer Treat. Rev. 99, 102257 (2021).
Emens, L. A. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer: biomarker evaluation of the IMpassion130 study. J. Natl Cancer Inst. 113, 1005–1016 (2021).
Bonneau, C. et al. A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer. Breast Cancer Res. 22, 76 (2020).
Aftimos, P. et al. Genomic and transcriptomic analyses of breast cancer primaries and matched metastases in AURORA, the Breast International Group (BIG) molecular screening initiative. Cancer Discov. 11, 2796–2811 (2021).
Garcia-Recio, S. et al. Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis. Nat. Cancer 4, 128–147 (2023).
Aran, D., Hu, Z. & Butte, A. J. xCell: digitally portraying the tissue cellular heterogeneity landscape. Genome Biol. 18, 220 (2017).
Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).
Adams, S. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397–404 (2019).
Brown, K. A. et al. Menopause is a determinant of breast aromatase expression and its associations with BMI, inflammation, and systemic markers. J. Clin. Endocrinol. Metab. 102, 1692–1701 (2017).
Dunbier, A. K. et al. Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women. J. Clin. Oncol. 28, 1161–1167 (2010).
Nanda, R. et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 6, 676–684 (2020).
Pusztai, L. et al. Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: results from the adaptively randomized I-SPY2 trial. Cancer Cell 39, 989–998.e5 (2021).
Voorwerk, L. et al. Immune landscape of breast tumors with low and intermediate estrogen receptor expression. NPJ Breast Cancer 9, 39 (2023).
Loi, S. et al. LBA20 a randomized, double-blind trial of nivolumab (NIVO) vs placebo (PBO) with neoadjuvant chemotherapy (NACT) followed by adjuvant endocrine therapy (ET) ± NIVO in patients (pts) with high-risk, ER+ HER2− primary breast cancer (BC). Ann. Oncol. 34, S1259–S1260 (2023).
Hanamura, T. et al. Expression of hormone receptors is associated with specific immunological profiles of the breast cancer microenvironment. Breast Cancer Res. 25, 13 (2023).
Quigley, D. A. et al. Age, estrogen, and immune response in breast adenocarcinoma and adjacent normal tissue. Oncoimmunology 6, e1356142 (2017).
Oesterreich, S. et al. Estrogen-mediated down-regulation of E-cadherin in breast cancer cells. Cancer Res. 63, 5203–5208 (2003).
Rae, J. M. & Lippman, M. E. The role of estrogen receptor signaling in suppressing the immune response to cancer. J. Clin. Invest. 131, e155476 (2021).
Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 7, 72–85 (2017).
Polanczyk, M. J. et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J. Immunol. 173, 2227–2230 (2004).
Polanczyk, M. J., Hopke, C., Vandenbark, A. A. & Offner, H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int. Immunol. 19, 337–343 (2007).
Hazlett, J. et al. Oestrogen deprivation induces chemokine production and immune cell recruitment in in vitro and in vivo models of oestrogen receptor-positive breast cancer. Breast Cancer Res. 23, 95 (2021).
Jacobson, D. L., Gange, S. J., Rose, N. R. & Graham, N. M. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol. 84, 223–243 (1997).
Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).
Schafer, J. M. et al. Sex-biased adaptive immune regulation in cancer development and therapy. iScience 25, 104717 (2022).
Ye, Y. et al. Sex-associated molecular differences for cancer immunotherapy. Nat. Commun. 11, 1779 (2020).
Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 13, 23–33 (2013).
Ander, S. E., Diamond, M. S. & Coyne, C. B. Immune responses at the maternal-fetal interface. Sci. Immunol. 4, eaat6114 (2019).
Shao, C. et al. Prognosis of pregnancy-associated breast cancer: a meta-analysis. BMC Cancer 20, 746 (2020).
Thomas, R., Wang, W. & Su, D. M. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun. Ageing 17, 2 (2020).
Thompson, E. et al. The immune microenvironment of breast ductal carcinoma in situ. Mod. Pathol. 29, 249–258 (2016).
Marongiu, F. & DeGregori, J. The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease. Mol. Oncol. 16, 3238–3258 (2022).
Berben, L. et al. Age-related remodelling of the blood immunological portrait and the local tumor immune response in patients with luminal breast cancer. Clin. Transl. Immunol. 9, e1184 (2020).
Qing, T. et al. Molecular differences between younger versus older ER-positive and HER2-negative breast cancers. NPJ Breast Cancer 8, 119 (2022).
Piccart, M. J. et al. Gene expression signatures for tailoring adjuvant chemotherapy of luminal breast cancer: stronger evidence, greater trust. Ann. Oncol. 32, 1077–1082 (2021).
Sun, H., Huang, W., Ji, F., Pan, Y. & Yang, L. Comparisons of metastatic patterns, survival outcomes and tumor immune microenvironment between young and non-young breast cancer patients. Front. Cell Dev. Biol. 10, 923371 (2022).
Sceneay, J. et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 9, 1208–1227 (2019).
Adams, S. et al. Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 405–411 (2019).
Garcia, M. G. et al. Immune checkpoint expression and relationships to anti-PD-L1 immune checkpoint blockade cancer immunotherapy efficacy in aged versus young mice. Aging Cancer 3, 68–83 (2022).
Stephens, P. J. et al. The landscape of cancer genes and mutational processes in breast cancer. Nature 486, 400–404 (2012).
Shin, H. C. et al. Detection of germline mutations in breast cancer patients with clinical features of hereditary cancer syndrome using a multi-gene panel test. Cancer Res. Treat. 52, 697–713 (2020).
Mak, T. W. et al. Brca1 required for T cell lineage development but not TCR loci rearrangement. Nat. Immunol. 1, 77–82 (2000).
Wu, B. et al. BRCA1 deficiency in mature CD8+ T lymphocytes impairs antitumor immunity. J. Immunother. Cancer 11, e005852 (2023).
Jeong, J. H., Jo, A., Park, P., Lee, H. & Lee, H. O. Brca2 deficiency leads to T cell loss and immune dysfunction. Mol. Cell 38, 251–258 (2015).
Barwell, J. et al. Lymphocyte radiosensitivity in BRCA1 and BRCA2 mutation carriers and implications for breast cancer susceptibility. Int. J. Cancer 121, 1631–1636 (2007).
Kote-Jarai, Z. et al. Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers. Br. J. Cancer 94, 308–310 (2006).
Nolan, E. et al. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci. Transl. Med. 9, eaal4922 (2017).
Sun, S. et al. Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers. J. Clin. Invest. 132, e148113 (2022).
Galluzzi, L., Kepp, O., Hett, E., Kroemer, G. & Marincola, F. M. Immunogenic cell death in cancer: concept and therapeutic implications. J. Transl. Med. 21, 162 (2023).
Ciampricotti, M., Hau, C.-S., Doornebal, C. W., Jonkers, J. & de Visser, K. E. Chemotherapy response of spontaneous mammary tumors is independent of the adaptive immune system. Nat. Med. 18, 344–346 (2012).
Jacob, S. L., Huppert, L. A. & Rugo, H. S. Role of immunotherapy in breast cancer. JCO Oncol. Pract. 19, 167–179 (2023).
Emens, L. A. et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study. JAMA Oncol. 5, 74–82 (2019).
Emens, L. A. & Loi, S. Immunotherapy approaches for breast cancer patients in 2023. Cold Spring Harb. Perspect. Med. 13, a041332 (2023).
Bianchini, G., De Angelis, C., Licata, L. & Gianni, L. Treatment landscape of triple-negative breast cancer — expanded options, evolving needs. Nat. Rev. Clin. Oncol. 19, 91–113 (2022).
Emens, L. A. et al. 296P tumour mutational burden and clinical outcomes with first-line atezolizumab and nab-paclitaxel in triple-negative breast cancer: exploratory analysis of the phase III IMpassion130 trial. Ann. Oncol. 31, S360–S361 (2020).
Dixon-Douglas, J., Loibl, S., Denkert, C., Telli, M. & Loi, S. Integrating immunotherapy into the treatment landscape for patients with triple-negative breast cancer. Am. Soc. Clin. Oncol. Educ. Book. 42, 1–13 (2022).
Shahbandi, A. et al. Breast cancer cells survive chemotherapy by activating targetable immune-modulatory programs characterized by PD-L1 or CD80. Nat. Cancer 3, 1513–1533 (2022).
Hodge, J. W. et al. Chemotherapy-induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death. Int. J. Cancer 133, 624–636 (2013).
Liu, W. M., Fowler, D. W., Smith, P. & Dalgleish, A. G. Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br. J. Cancer 102, 115–123 (2010).
Emens, L. A. et al. The tumor microenvironment (TME) and atezolizumab + nab-paclitaxel (A+nP) activity in metastatic triple-negative breast cancer (mTNBC): IMpassion130. J. Clin. Oncol. 39, 1006 (2021).
Winship, A. L. et al. Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in mice. Nat. Cancer 3, 1–13 (2022).
Loibl, S. et al. Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response. Ann. Oncol. 33, 1149–1158 (2022).
Liu, J. et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 6, 1382–1399 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03498716 (2018).
Barrios, C. H. et al. Final analysis of the placebo-controlled randomised phase 3 IMpassion031 trial evaluating neoadjuvant atezolizumab (atezo) plus chemotherapy (CT) followed by open-label adjuvant atezo in patients (pts) with early-stage triple-negative breast cancer (eTNBC). Annals Oncol. 8, abstr. LBA1, 101220-101220 (2023).
Ademuyiwa, F. O. et al. A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013. NPJ Breast Cancer 8, 134 (2022).
Sharma, P. et al. Clinical and biomarker findings of neoadjuvant pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer: NeoPACT phase 2 clinical trial. JAMA Oncol. 10, 227–235 (2023).
Loi, S. et al. Randomized Phase II Study of Neoadjuvant Nivolumab (N) 2 week lead-in followed by 12 weeks of concurrent N+carboplatin plus paclitaxel (CbP) vs concurrent N+CbP in Triple Negative Breast Cancer (TNBC): (BCT1902/IBCSG 61-20 Neo-N). Cancer Res. 84, abstr. LBO1–03, https://doi.org/10.1158/1538-7445.SABCS23-LBO1-03 (2024).
Cardoso, F. et al. LBA21 KEYNOTE-756: phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2− breast cancer. Ann. Oncol. 34, S1260–S1261 (2023).
Dieci, M. V. et al. Neoadjuvant chemotherapy and immunotherapy in luminal B-like breast cancer: results of the phase II GIADA trial. Clin. Cancer Res. 28, 308–317 (2022).
Rugo, H. S. et al. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Clin. Cancer Res. 24, 2804–2811 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03725059 (2018).
Merck. Merck announces phase 3 KEYNOTE-756 trial met primary endpoint of pathological complete response (pCR) rate in patients with high-risk, early-stage ER+/HER2- breast cancer. Merck https://www.merck.com/news/merck-announces-phase-3-keynote-756-trial-met-primary-endpoint-of-pathological-complete-response-pcr-rate-in-patients-with-high-risk-early-stage-er-her2-breast-cancer/ (2023).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03879174 (2019).
US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT03393845 (2018).
US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT03874325 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03280563 (2017).
US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT02778685 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT02779751 (2016).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03294694 (2017).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03573648 (2018).
Weigelt, B., Eberle, C., Cowell, C. F., Ng, C. K. & Reis-Filho, J. S. Metaplastic breast carcinoma: more than a special type. Nat. Rev. Cancer 14, 147–148 (2014).
Adams, S. et al. A multicenter phase II trial of ipilimumab and nivolumab in unresectable or metastatic metaplastic breast cancer: cohort 36 of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART, SWOG S1609). Clin. Cancer Res. 28, 271–278 (2022).
Roussos Torres, E. T. et al. Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial. Nat. Cancer https://doi.org/10.1038/s43018-024-00729-w (2024).
Loi, S. et al. Neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant early-stage triple-negative breast cancer (TNBC): a single-arm phase 2 trial. J. Clin. Oncol. 40, 602 (2022).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03726879 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04873362 (2021).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04348643 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03682744 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03696030 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03740256 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04430595 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04511871 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02792114 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02414269 (2015).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04025216 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04020575 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04107142 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02706392 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02830724 (2017).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02541370 (2015).
Jung, I. Y. et al. Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors. Cell Rep. Med. 4, 101053 (2023).
Zacharakis, N. et al. Breast cancers are immunogenic: immunologic analyses and a phase II pilot clinical trial using mutation-reactive autologous lymphocytes. J. Clin. Oncol. 40, 1741–1754 (2022).
Ayoub, N. M., Jaradat, S. K., Al-Shami, K. M. & Alkhalifa, A. E. Targeting angiogenesis in breast cancer: current evidence and future perspectives of novel anti-angiogenic approaches. Front. Pharmacol. 13, 838133 (2022).
Salgado, R. & Loi, S. What’s in a name? That which we call immune cells by any other name would all smell as sweet. Clin. Cancer Res. 28, 2728–2729 (2022).
US National Library of Medicine. ClinicalTrials.gov https://classic.clinicaltrials.gov/ct2/show/NCT04739670 (2021).
Timperi, E. et al. Lipid-associated macrophages are induced by cancer-associated fibroblasts and mediate immune suppression in breast cancer. Cancer Res. 82, 3291–3306 (2022).
House, I. G. et al. Macrophage-derived CXCL9 and CXCL10 are required for antitumor immune responses following immune checkpoint blockade. Clin. Cancer Res. 26, 487–504 (2020).
Linde, N. et al. Macrophages orchestrate breast cancer early dissemination and metastasis. Nat. Commun. 9, 21 (2018).
Lin, H. et al. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320, 807–811 (2008).
Autio, K. A. et al. Immunomodulatory activity of a colony-stimulating factor-1 receptor inhibitor in patients with advanced refractory breast or prostate cancer: a phase I study. Clin. Cancer Res. 26, 5609–5620 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03335540 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03431948 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02435680 (2015).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03742349 (2019).
Terranova-Barberio, M. et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat. Commun. 11, 3584 (2020).
Matsumoto, H. et al. Increased CD4 and CD8-positive T cell infiltrate signifies good prognosis in a subset of triple-negative breast cancer. Breast Cancer Res. Treat. 156, 237–247 (2016).
Ladoire, S. et al. T-bet expression in intratumoral lymphoid structures after neoadjuvant trastuzumab plus docetaxel for HER2-overexpressing breast carcinoma predicts survival. Br. J. Cancer 105, 366–371 (2011).
Gu-Trantien, C. et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J. Clin. Invest. 123, 2873–2892 (2013).
Plitas, G. et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 45, 1122–1134 (2016).
Alizadeh, D. et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Cancer Res. 74, 104–118 (2014).
Mattarollo, S. R. et al. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71, 4809–4820 (2011).
Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02499367 (2015).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02819518 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03639948 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02883062 (2017).
Kodumudi, K. N. et al. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin. Cancer Res. 16, 4583–4594 (2010).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03881878 (2019).
Ahn, H. K. et al. Response rate and safety of a neoadjuvant pertuzumab, atezolizumab, docetaxel, and trastuzumab regimen for patients with ERBB2-positive stage II/III breast cancer: the Neo-PATH phase 2 nonrandomized clinical trial. JAMA Oncol. 8, 1271–1277 (2022).
Wanderley, C. W. et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res. 78, 5891–5900 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02425891 (2015).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02685059 (2016).
Heylmann, D. et al. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS ONE 8, e83384 (2013).
Zhao, J. et al. Selective depletion of CD4+CD25+Foxp3+ regulatory T cells by low-dose cyclophosphamide is explained by reduced intracellular ATP levels. Cancer Res. 70, 4850–4858 (2010).
Dimeloe, S. et al. Human regulatory T cells lack the cyclophosphamide-extruding transporter ABCB1 and are more susceptible to cyclophosphamide-induced apoptosis. Eur. J. Immunol. 44, 3614–3620 (2014).
Huober, J. et al. Atezolizumab with neoadjuvant anti-human epidermal growth factor receptor 2 therapy and chemotherapy in human epidermal growth factor receptor 2-positive early breast cancer: primary results of the randomized phase III IMpassion050 trial. J. Clin. Oncol. 40, 2946–2956 (2022).
Richards, J. O., Albers, A. J., Smith, T. S. & Tjoe, J. A. NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells. Cancer Immunol. Immunother. 65, 1325–1335 (2016).
Chan, M. S. et al. Changes of tumor infiltrating lymphocyte subtypes before and after neoadjuvant endocrine therapy in estrogen receptor-positive breast cancer patients — an immunohistochemical study of Cd8+ and Foxp3+ using double immunostaining with correlation to the pathobiological response of the patients. Int. J. Biol. Markers 27, e295–e304 (2012).
Generali, D. et al. Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin. Cancer Res. 15, 1046–1051 (2009).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT04109066 (2019).
Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017).
Hurvitz, S. A. et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR+/HER2− breast cancer. Clin. Cancer Res. 26, 566–580 (2020).
Rugo, H. S. et al. Abemaciclib in combination with pembrolizumab for HR+, HER2− metastatic breast cancer: phase 1b study. NPJ Breast Cancer 8, 118 (2022).
Kaneda, M. M. et al. PI3Kγ is a molecular switch that controls immune suppression. Nature 539, 437–442 (2016).
De Henau, O. et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature 539, 443–447 (2016).
Sai, J. et al. PI3K inhibition reduces mammary tumor growth and facilitates antitumor immunity and anti-PD1 responses. Clin. Cancer Res. 23, 3371–3384 (2017).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03961698 (2019).
Hatem, S. et al. Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC). Cancer Res. 82, abstr. P5-P16-02 (2022).
Marks, D. K. et al. Akt inhibition is associated with favorable immune profile changes within the tumor microenvironment of hormone receptor positive, HER2 negative breast cancer. Front. Oncol. 10, 968 (2020).
Bullock, K. K. et al. Endogenous pAKT activity is associated with response to AKT inhibition alone and in combination with immune checkpoint inhibition in murine models of TNBC. Cancer Lett. 586, 216681 (2024).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03800836 (2018).
Schmid, P. et al. First-line ipatasertib, atezolizumab, and taxane triplet for metastatic triple-negative breast cancer: clinical and biomarker results. Clin. Cancer Res. 30, 767–778 (2024).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03337724 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04177108 (2019).
Mehta, A. K. et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat. Cancer 2, 66–82 (2021).
Wang, L. et al. PARP-inhibition reprograms macrophages toward an anti-tumor phenotype. Cell Rep. 41, 111462 (2022).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02734004 (2016).
Domchek, S. M. et al. Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Lancet Oncol. 21, 1155–1164 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT01042379 (2010).
Wang, Z. et al. Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models. Sci. Rep. 9, 1853 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02657889 (2016).
Vinayak, S. et al. Open-label clinical trial of niraparib combined with pembrolizumab for treatment of advanced or metastatic triple-negative breast cancer. JAMA Oncol. 5, 1132–1140 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03330405 (2017).
Yap, T. A. et al. Avelumab plus talazoparib in patients with advanced solid tumors: the JAVELIN PARP Medley nonrandomized controlled trial. JAMA Oncol. 9, 40–50 (2023).
Iwata, T. N., Sugihara, K., Wada, T. & Agatsuma, T. [Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model. PLoS ONE 14, e0222280 (2019).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03523572 (2018).
Hamilton, E. et al. Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: a 2-part, phase 1b, multicenter, open-label study. Cancer Res. 81, abstr. PD3-07, https://doi.org/10.1158/1538-7445.SABCS20-PD3-07 (2021).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03742102 (2018).
Schmid, P. et al. PD11-08 trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study. Cancer Res. 83, abstr. PD11-08 (2023).
Müller, P. et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci. Transl. Med. 7, 315ra188 (2015).
Hamilton, E. P. et al. Impact of anti-HER2 treatments combined with atezolizumab on the tumor immune microenvironment in early or metastatic breast cancer: results from a phase Ib study. Clin. Breast Cancer 21, 539–551 (2021).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02924883 (2016).
Emens, L. A. et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 21, 1283–1295 (2020).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT02605915 (2015).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/study/NCT03032107 (2017).
Waks, A. G. et al. Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer. J. Immunother. Cancer 10, e005119 (2022).
Schmid, P. et al. Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase Ib/II study. Ann. Oncol. 34, S337, abstr. 379MO (2023).
Hammond, M. E. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J. Clin. Oncol. 28, 2784–2795 (2010).
Fu, N. Y. et al. Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive. Nat. Cell Biol. 19, 164–176 (2017).
Lim, E. et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat. Med. 15, 907–913 (2009).
Hu, L. et al. Single-Cell RNA sequencing reveals the cellular origin and evolution of breast cancer in BRCA1 mutation carriers. Cancer Res. 81, 2600–2611 (2021).
Nguyen, Q. H. et al. Profiling human breast epithelial cells using single cell RNA sequencing identifies cell diversity. Nat. Commun. 9, 2028 (2018).
Ding, Y. et al. Cell lineage tracing links ERα loss in Erbb2-positive breast cancers to the arising of a highly aggressive breast cancer subtype. Proc. Natl Acad. Sci. USA 118, e2100673118 (2021).
McCart Reed, A. E., Kutasovic, J. R., Lakhani, S. R. & Simpson, P. T. Invasive lobular carcinoma of the breast: morphology, biomarkers and ‘omics. Breast Cancer Res. 17, 12 (2015).
Arpino, G., Bardou, V. J., Clark, G. M. & Elledge, R. M. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 6, R149–R156 (2004).
Casasent, A. K. et al. Learning to distinguish progressive and non-progressive ductal carcinoma in situ. Nat. Rev. Cancer 22, 663–678 (2022).
Siracusa, F., Tintelnot, J., Cortesi, F. & Gagliani, N. Diet and immune response: how today’s plate shapes tomorrow’s health. Trends Immunol. 45, 4–10 (2023).
McIntyre, C. L., Temesgen, A. & Lynch, L. Diet, nutrient supply, and tumor immune responses. Trends Cancer 9, 752–763 (2023).
Swaby, A., Atallah, A., Varol, O., Cristea, A. & Quail, D. F. Lifestyle and host determinants of antitumor immunity and cancer health disparities. Trends Cancer 9, 1019–1040 (2023).
Koivula, T. et al. The effect of acute exercise on circulating immune cells in newly diagnosed breast cancer patients. Sci. Rep. 13, 6561 (2023).
Bruinsma, T. J., Dyer, A.-M., Rogers, C. J., Schmitz, K. H. & Sturgeon, K. M. Effects of diet and exercise-induced weight loss on biomarkers of inflammation in breast cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol. Biomark. Prev. 30, 1048–1062 (2021).
Devi, S. et al. Adrenergic regulation of the vasculature impairs leukocyte interstitial migration and suppresses immune responses. Immunity 54, 1219–1230.e17 (2021).
Hiller, J. G. et al. Preoperative β-blockade with propranolol reduces biomarkers of metastasis in breast cancer: a phase II randomized trial. Clin. Cancer Res. 26, 1803–1811 (2020).
Pan, J. W. et al. The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences. Nat. Commun. 11, 6433 (2020).
Roy, A. M. et al. Racial and ethnic disparity in preoperative chemosensitivity and survival in patients with early-stage breast cancer. JAMA Netw. Open 6, e2344517 (2023).
Shubeck, S., Zhao, F., Howard, F. M., Olopade, O. I. & Huo, D. Response to treatment, racial and ethnic disparity, and survival in patients with breast cancer undergoing neoadjuvant chemotherapy in the US. JAMA Netw. Open 6, e235834 (2023).
Beral, V. et al. Collaborative group on hormonal factors in breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360, 187–195 (2002).
El Tekle, G. & Garrett, W. S. Bacteria in cancer initiation, promotion and progression. Nat. Rev. Cancer 23, 600–618 (2023).
Thompson, P. A. et al. Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 36, S232–S253 (2015).
Hoffmann, J. P., Liu, J. A., Seddu, K. & Klein, S. L. Sex hormone signaling and regulation of immune function. Immunity 56, 2472–2491 (2023).
Passarelli, M. N. et al. Cigarette smoking before and after breast cancer diagnosis: mortality from breast cancer and smoking-related diseases. J. Clin. Oncol. 34, 1315–1322 (2016).
Tyagi, A. et al. Nicotine promotes breast cancer metastasis by stimulating N2 neutrophils and generating pre-metastatic niche in lung. Nat. Commun. 12, 474 (2021).
Liu, Y. et al. Dysregulation of immunity by cigarette smoking promotes inflammation and cancer: a review. Environ. Pollut. 339, 122730 (2023).
McQuade, J. L. et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 19, 310–322 (2018).
Garbarino, S., Lanteri, P., Bragazzi, N. L., Magnavita, N. & Scoditti, E. Role of sleep deprivation in immune-related disease risk and outcomes. Commun. Biol. 4, 1304 (2021).
IARC Monographs Vol 124 group. Carcinogenicity of night shift work. Lancet Oncol. 20, 1058–1059 (2019).
McDonald, K. A. et al. Tumor heterogeneity correlates with less immune response and worse survival in breast cancer patients. Ann. Surg. Oncol. 26, 2191–2199 (2019).
Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat. Med. 27, 212–224 (2021).
Yndestad, S. et al. Homologous recombination deficiency across subtypes of primary breast cancer. JCO Precis. Oncol. 7, e2300338 (2023).
Budczies, J. et al. Homologous recombination deficiency is inversely correlated with microsatellite instability and identifies immunologically cold tumors in most cancer types. J. Pathol. Clin. Res. 8, 371–382 (2022).
Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
Marabelle, A. et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21, 1353–1365 (2020).
Winer, E. P. et al. Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol. 22, 499–511 (2021).
Barroso-Sousa, R. et al. Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann. Oncol. 31, 387–394 (2020).
Karn, T. et al. Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo. Ann. Oncol. 31, 1216–1222 (2020).
Emami Nejad, A. et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell Int. 21, 62 (2021).
Noer, J. B., Hørsdal, O. K., Xiang, X., Luo, Y. & Regenberg, B. Extrachromosomal circular DNA in cancer: history, current knowledge, and methods. Trends Genet. 38, 766–781 (2022).
Wu, S., Bafna, V., Chang, H. Y. & Mischel, P. S. Extrachromosomal DNA: an emerging hallmark in human cancer. Annu. Rev. Pathol. 17, 367–386 (2022).
Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).
Cortes, J. et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 396, 1817–1828 (2020).
Sompuram, S. R., Torlakovic, E. E., t Hart, N. A., Vani, K. & Bogen, S. A. Quantitative comparison of PD-L1 IHC assays against NIST standard reference material 1934. Mod. Pathol. 35, 326–332 (2022).
Islami, F. et al. Breastfeeding and breast cancer risk by receptor status-a systematic review and meta-analysis. Ann. Oncol. 26, 2398–2407 (2015).
Johansson, A. L. V. & Stensheim, H. Epidemiology of pregnancy-associated breast cancer. Adv. Exp. Med. Biol. 1252, 75–79 (2020).
Hartman, E. K. & Eslick, G. D. The prognosis of women diagnosed with breast cancer before, during and after pregnancy: a meta-analysis. Breast Cancer Res. Treat. 160, 347–360 (2016).
Pilewskie, M. et al. Association between recency of last pregnancy and biologic subtype of breast cancer. Ann. Surg. Oncol. 19, 1167–1173 (2012).
Sajjadi, E. et al. Breast cancer during pregnancy as a special type of early-onset breast cancer: analysis of the tumor immune microenvironment and risk profiles. Cells 11, 2286 (2022).
Johansson, A. L. V. et al. Tumor characteristics and prognosis in women with pregnancy-associated breast cancer. Int. J. Cancer 142, 1343–1354 (2018).
Schedin, P., O’Brien, J., Rudolph, M., Stein, T. & Borges, V. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J. Mammary Gland Biol. Neoplasia 12, 71–82 (2007).
Martinson, H. A., Jindal, S., Durand-Rougely, C., Borges, V. F. & Schedin, P. Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression. Int. J. Cancer 136, 1803–1813 (2015).
Jindal, S. et al. Postpartum breast cancer has a distinct molecular profile that predicts poor outcomes. Nat. Commun. 12, 6341 (2021).
Azim, H. A. Jr. et al. Tumour infiltrating lymphocytes (TILs) in breast cancer during pregnancy. Breast 24, 290–293 (2015).
Acknowledgements
The authors are extremely grateful to T. Geukens, N. Chic, A. Makhale and M. Hun for their contributions, providing insightful feedback from their respective areas of expertise and invaluable discussions. The authors thank J. Parrodi for her assistance in administration, organizing and formatting of the manuscript. R.S. is supported by the Breast Cancer Research Foundation (BCRF, grant number 17-194). S.L. is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York.
Author information
Authors and Affiliations
Contributions
M.A.H., P.S., M.M.R.O. and S.L. researched data for the article. All authors contributed substantially to discussion of the content. M.A.H., P.S. and S.L. wrote the article. All authors reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
P.S. receives funding to institution from Roche-Genentech. R.S. reports non-financial support from Merck and Bristol Myers Squibb (BMS), research support from Merck, Puma Biotechnology and Roche, and personal fees from Roche, BMS, Astra Zeneca, Daicchii Sankyo and Exact Sciences for advisory boards. S.L. receives research funding to institution from Novartis, Bristol Myers Squibb, MSD, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca/Daiichi Sankyo and Seattle Genetics. S.L. has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, MSD, AstraZeneca–Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies and Roche-Genentech. S.L. has acted as consultant (paid to institution) to Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca–Daiichi Sankyo, Gilead Sciences, Seattle Genetics, Merck Sharp and Dohme, Eli Lilly and Bristol Myers Squibb. All other authors declare no conflicts.
Peer review
Peer review information
Nature Reviews Cancer thanks the anonymous reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
ASCO cap guidelines: https://society.asco.org/practice-patients/guidelines/breast-cancer
TIL assessment in breast cancer: www.tilsinbreastcancer.org
Glossary
- Aromatase
-
Enzyme involved in oestrogen production.
- CD3+ T cells
-
Encompasses both CD4+ and CD8+ T cells and a subset of natural killer (NK) cells.
- CD4+ T cells
-
Includes T helper cells and Treg cells.
- CD8+ T cells
-
Includes cytotoxic T cells which directly kill tumour or infected cells and stem-like T cells.
- CD8+ tissue-resident memory-like T cells
-
(TRM-like cells). A subpopulation of CD8+ T cells that has a role in peripheral immune surveillance and persists in tissue.
- Damage-associated molecular patterns
-
Molecules that are released from dying cells and activate pattern recognition receptors on innate immune cells.
- High endothelial venules
-
A type of blood vessel involved in lymphocyte trafficking.
- Immune scores
-
A gene expression signature indicating immune infiltration.
- Immunosenescence
-
The decline of immune function associated with ageing.
- Invasive ductal carcinoma
-
(IDC). The most common type of breast cancer which begins in the epithelial cells that line the milk ducts.
- Invasive lobular carcinoma
-
(ILC). A less common type of breast cancer that begins in the cells that line the lobules which are the glands responsible for milk production.
- M1-like macrophages
-
Macrophages that promote antitumour immunity through cytokine production and antigen presentation.
- M2-like macrophage
-
A macrophage that facilitate tumour growth by dampening the adaptive immune response.
- Merck’s Combined Positive Score (CPS) assay
-
An immunohistochemical assay to assess programmed cell death ligand 1 (PDL1) expression.
- Multiplexed ion beam imaging
-
Imaging technology that allows for the spatial analysis in a sample with a high number of parameters by using mass spectrometry to detect metal-tagged antibodies, as opposed to antibodies conventionally tagged with fluorophores.
- Oophorectomized mice
-
Mice that have had their ovaries surgically removed.
- T cell-inflamed gene expression profile
-
A gene signature indicating a cytotoxic T cell response.
- T cell-specific transcription factor 1
-
(TCF1). A critical marker for precursors to exhausted effector cells which display dynamic states of exhaustion and dysfunction.
- T follicular helper cells
-
A subset of CD4+ T cells that can activate B cells.
- Tertiary lymphoid structures
-
(TLSs). An aggregate of immune cells with an ordered structure in non-lymphoid tissue.
- Tumour-infiltrating lymphocyte
-
Broadly defined as T and B lymphocytes that have infiltrated the tumour microenvironment.
- Type 2 conventional DCs
-
A subtype of dendritic cell (DC) that promotes adaptive immunity.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Harris, M.A., Savas, P., Virassamy, B. et al. Towards targeting the breast cancer immune microenvironment. Nat Rev Cancer (2024). https://doi.org/10.1038/s41568-024-00714-6
Accepted:
Published:
DOI: https://doi.org/10.1038/s41568-024-00714-6
