Skip to main content
SpringerLink
Log in

Immunobiology of Testicular Cancer

  • Chapter
  • First Online:
Interdisciplinary Cancer Research

Part of the book series: Interdisciplinary Cancer Research

Abstract

Testicular cancer is one of the most common oncological diseases in young men aged from 14 to 44 years and accounts for approximately 1% of cancer diagnoses worldwide. There is widely varying participation of the immune system between patients arising from the combination of different testicular cancer subtypes within testicular germ cell tumours (i.e. seminoma and non-seminoma) and the normal function of the testis as an immune-privileged organ. In this regard, it is not quite clear if the different immune cells, their subtypes, and respective cytokines and chemokines act as friends or foes when it comes to tumour progression and prognosis. Increasing focus on immune cell presence and their contribution to the tumour microenvironment has stimulated a plethora of studies on other cancer entities; however, our knowledge concerning testis cancer remains limited. Databases have been searched by using keywords ‘testicular germ cell tumor’, ‘immune cells in TGCT’, ‘testis immune privilege’, ‘TIL’, ‘Tumour infiltrating immune cells’, and ‘tumour microenvironment’. There is ample evidence that immune cells (including their subtypes, phenotypical polarisations, and cytokine/chemokine profiles) play an essential role not only in the healthy testis but also in testicular germ cell tumours. Complex interactions between immune cells, other testicular somatic cells, and neoplastic germ cells actively shape a testis-specific tumour microenvironment, which affects tumour growth, metastatic behaviour, and also drug resistance. Intensive research is now being performed to identify immune cell-related risk scores, with the goal of estimating the impact on patients’ prognosis and developing new immune-based therapies. This chapter aims to summarise the up-to-date knowledge of the involvement of immune cells in testicular cancer and includes a brief overview of immune privilege of the testis, development of testicular germ cell tumours, and different methods to assess immune cell presence and activity.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Alberts E, Wall I, Calado DP, Grigoriadis A (2021) Immune crosstalk between lymph nodes and breast carcinomas, with a focus on B cells. Front Mol Biosci 8:673051

    Google Scholar 

  • Aras S, Zaidi MR (2017) TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer 117(11):1583–1591

    Google Scholar 

  • Balan S, Saxena M, Bhardwaj N (2019) Dendritic cell subsets and locations. Int Rev Cell Mol Biol 348:1–68

    Google Scholar 

  • Barnes TA, Amir E (2017) HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer. Br J Cancer 117(4):451–460

    Google Scholar 

  • Batool A, Karimi N, Wu X-N, Chen S-R, Liu Y-X (2019a) Testicular germ cell tumor. A comprehensive review. Cell Mol Life Sci 76(9):1713–1727

    Google Scholar 

  • Batool A, Liu X-M, Zhang C-L, Hao C-F, Chen S-R, Liu Y-X (2019b) Recent advances in the regulation of testicular germ cell tumors by microRNAs. Front Biosci (Landmark Edition) 24:765–776

    Google Scholar 

  • Bell DA, Flotte TJ, Bhan AK (1987) Immunohistochemical characterization of seminoma and its inflammatory cell infiltrate. Hum Pathol 18(5):511–520

    Google Scholar 

  • Bergh A (1987) Treatment with hCG increases the size of Leydig cells and testicular macrophages in unilaterally cryptorchid rats. Int J Androl 10(6):765–772

    Google Scholar 

  • Bergmann M, Dierichs R (1983) Postnatal formation of the blood-testis barrier in the rat with special reference to the initiation of meiosis. Anat Embryol 168(2):269–275

    Google Scholar 

  • Berney DM, Looijenga LHJ, Idrees M, Oosterhuis JW, Rajpert-De Meyts E, Ulbright TM, Skakkebaek NE (2016) Germ cell neoplasia in situ (GCNIS): evolution of the current nomenclature for testicular pre-invasive germ cell malignancy. Histopathology 69(1):7–10

    Google Scholar 

  • Bhushan S, Theas MS, Guazzone VA, Jacobo P, Wang M, Fijak M, Meinhardt A, Lustig L (2020) Immune cell subtypes and their function in the testis. Front Immunol 11:583304

    Google Scholar 

  • Białas M, Fiszer D, Rozwadowska N, Kosicki W, Jedrzejczak P, Kurpisz M (2009) The role of IL-6, IL-10, TNF-alpha and its receptors TNFR1 and TNFR2 in the local regulatory system of normal and impaired human spermatogenesis. Am J Reprod Immunol (New York, N.Y.: 1989) 62(1):51–59

    Google Scholar 

  • Black CB, Duensing TD, Trinkle LS, Dunlay RT (2011) Cell-based screening using high-throughput flow cytometry. Assay Drug Dev Technol 9(1):13–20

    Google Scholar 

  • Blanchard L, Girard J-P (2021) High endothelial venules (HEVs) in immunity, inflammation and cancer. Angiogenesis 24(4):719–753

    Google Scholar 

  • Bols B, Jensen L, Jensen A, Braendstrup O (2000) Immunopathology of in situ seminoma. Int J Exp Pathol 81(3):211–217

    Google Scholar 

  • Broketa M, Bruhns P (2021) Single-cell Technologies for the Study of antibody-secreting cells. Front Immunol 12:821729

    Google Scholar 

  • Cancro MP, Tomayko MM (2021) Memory B cells and plasma cells: the differentiative continuum of humoral immunity. Immunol Rev 303(1):72–82

    Google Scholar 

  • Chen H, Murray E, Sinha A, Laumas A, Li J, Lesman D, Nie X, Hotaling J, Guo J, Cairns BR, Macosko EZ, Cheng CY, Chen F (2021) Dissecting mammalian spermatogenesis using spatial transcriptomics. Cell Rep 37(5):109915

    Google Scholar 

  • Cheng CY, Mruk DD (2012) The blood-testis barrier and its implications for male contraception. Pharmacol Rev 64(1):16–64

    Google Scholar 

  • Cheng L, Albers P, Berney DM, Feldman DR, Daugaard G, Gilligan T, Looijenga LHJ (2018) Testicular cancer. Nat Rev Dis Primers 4(1):29

    Google Scholar 

  • Chovanec M, Mardiak J, Mego M (2019) Immune mechanisms and possible immune therapy in testicular germ cell tumours. Andrology 7(4):479–486

    Google Scholar 

  • Collin M, Bigley V (2018) Human dendritic cell subsets: an update. Immunology 154(1):3–20

    Google Scholar 

  • Dias V, Meachem S, Rajpert-De Meyts E, McLachlan R, Manuelpillai U, Loveland KL (2008) Activin receptor subunits in normal and dysfunctional adult human testis. Hum Reprod 23(2):412–420

    Google Scholar 

  • Dias VL, Rajpert-De Meyts E, McLachlan R, Loveland KL (2009) Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas. Reproduction 138(5):801–811

    Google Scholar 

  • Díez-Torre A, Silván U, Díaz-Núñez M, Aréchaga J (2010) The role of microenvironment in testicular germ cell tumors. Cancer Biol Ther 10(6):529–536

    Google Scholar 

  • Dinarello CA (2000) Proinflammatory cytokines. Chest 118(2):503–508

    Google Scholar 

  • Disis ML (2010) Immune regulation of cancer. J Clin Oncol 28(29):4531–4538

    Google Scholar 

  • Duan Y-G, Yu C-F, Novak N, Bieber T, Zhu C-H, Schuppe H-C, Haidl G, Allam J-P (2011) Immunodeviation towards a Th17 immune response associated with testicular damage in azoospermic men. Int J Androl 34(6 Pt 2):e536–e545

    Google Scholar 

  • Dym M, Fawcett DW (1970) The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol Reprod 3(3):308–326

    Google Scholar 

  • Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, Znaor A, Bray F (2019) Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144(8):1941–1953

    Google Scholar 

  • Fietz D, Kliesch S (2022) Testicular biopsy and histology. In: Nieschlag E, Behre HM, Nieschlag S (eds) Andrology. Male reproductive health and dysfunction. Springer, Berlin, Heidelberg. in press

    Google Scholar 

  • Fijak M, Meinhardt A (2006) The testis in immune privilege. Immunol Rev 213:66–81

    Google Scholar 

  • Fijak M, Pilatz A, Hedger MP, Nicolas N, Bhushan S, Michel V, Tung KSK, Schuppe H-C, Meinhardt A (2018) Infectious, inflammatory and 'autoimmune' male factor infertility: how do rodent models inform clinical practice? Hum Reprod Update 24(4):416–441

    Google Scholar 

  • Foster RS, Rubin LR, McNulty A, Bihrle R, Donohue JP (1991) Detection of antisperm-antibodies in patients with primary testicular cancer. Int J Androl 14(3):179–185

    Google Scholar 

  • França LR, Hess RA, Dufour JM, Hofmann MC, Griswold MD (2016) The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology 4(2):189–212

    Google Scholar 

  • Gajewski TF, Schreiber H, Fu Y-X (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Google Scholar 

  • Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc P-H, Trajanoski Z, Fridman W-H, Pagès F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964

    Google Scholar 

  • Gao J, Wang X, Wang Y, Han F, Cai W, Zhao B, Li Y, Han S, Wu X, Hu D (2016) Murine Sertoli cells promote the development of tolerogenic dendritic cells: a pivotal role of galectin-1. Immunology 148(3):253–265

    Google Scholar 

  • Gavrielatou N, Vathiotis I, Economopoulou P, Psyrri A (2021) The role of B cells in head and neck cancer. Cancers 13(21):5383. https://pubmed.ncbi.nlm.nih.gov/34771546/

  • Gaytan F, Bellido C, Aguilar E, van Rooijen N (1994) Requirement for testicular macrophages in Leydig cell proliferation and differentiation during prepubertal development in rats. J Reprod Fertil 102(2):393–399

    Google Scholar 

  • Gilbert DC, Chandler I, McIntyre A, Goddard NC, Gabe R, Huddart RA, Shipley J (2009) Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents. J Pathol 217(1):94–102

    Google Scholar 

  • Golubovskaya V, Wu L (2016) Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancers 8(3):36. https://pubmed.ncbi.nlm.nih.gov/26999211/

  • Grobholz R, Verbeke CS, Schleger C, Köhrmann KU, Hein B, Wolf G, Bleyl U, Spagnoli GC, Coplan K, Kolb D, Iversen K, Jungbluth AA (2000) Expression of MAGE antigens and analysis of the inflammatory T-cell infiltrate in human seminoma. Urol Res 28(6):398–403

    Google Scholar 

  • Grogg J, Schneider K, Bode PK, Kranzbühler B, Eberli D, Sulser T, Lorch A, Beyer J, Hermanns T, Fankhauser CD (2020) Sertoli cell tumors of the testes: systematic literature review and meta-analysis of outcomes in 435 patients. Oncologist 25(7):585–590

    Google Scholar 

  • Guo J, Grow EJ, Mlcochova H, Maher GJ, Lindskog C, Nie X, Guo Y, Takei Y, Yun J, Cai L, Kim R, Carrell DT, Goriely A, Hotaling JM, Cairns BR (2018) The adult human testis transcriptional cell atlas. Cell Res 28(12):1141–1157

    Google Scholar 

  • Gurney JK, Florio AA, Znaor A, Ferlay J, Laversanne M, Sarfati D, Bray F, McGlynn KA (2019) International trends in the incidence of testicular cancer: lessons from 35 years and 41 countries. Eur Urol 76(5):615–623

    Google Scholar 

  • Haabeth OAW, Lorvik KB, Hammarström C, Donaldson IM, Haraldsen G, Bogen B, Corthay A (2011) Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer. Nat Commun 2:240

    Google Scholar 

  • Hadrup SR, Braendstrup O, Jacobsen GK, Mortensen S, Pedersen LØ, Seremet T, Andersen MH, Becker JC, Straten PT (2006) Tumor infiltrating lymphocytes in seminoma lesions comprise clonally expanded cytotoxic T cells. Int J Cancer 119(4):831–838

    Google Scholar 

  • Han A-R, Lee JY, Kim H-J, Min W-S, Park G, Kim S-H (2015) A CXCR4 antagonist leads to tumor suppression by activation of immune cells in a leukemia-induced microenvironment. Oncol Rep 34(6):2880–2888

    Google Scholar 

  • Hedger MP (2002) Macrophages and the immune responsiveness of the testis. J Reprod Immunol 57(1–2):19–34

    Google Scholar 

  • Hedger MP (2012) Immune privilege of the testis: meaning, mechanisms, and manifestations. In: Stein-Streilein J (ed) Infection, immune homeostasis and immune privilege. Springer, Basel/New York, pp 31–52

    Google Scholar 

  • Hedger MP (2015) The Immunophysiology of male reproduction. In: Plant TM, Zeleznik A, Knobil E (eds) Knobil and Neill’s physiology of reproduction. Academic Press, Amsterdam, pp 805–892

    Google Scholar 

  • Hedger MP, Winnall WR (2012) Regulation of activin and inhibin in the adult testis and the evidence for functional roles in spermatogenesis and immunoregulation. Mol Cell Endocrinol 359(1–2):30–42

    Google Scholar 

  • Holstein AF, Schirren C, Roosen-Runge EC (eds) (1988) Illustrated pathology of human spermatogenesis. Grosse, Berlin

    Google Scholar 

  • Huang Y, Ma C, Zhang Q, Ye J, Wang F, Zhang Y, Hunborg P, Varvares MA, Hoft DF, Hsueh EC, Peng G (2015) CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget 6(19):17462–17478

    Google Scholar 

  • Hvarness T, Nielsen JE, Almstrup K, Skakkebaek NE, Rajpert-De Meyts E, Claesson MH (2013) Phenotypic characterisation of immune cell infiltrates in testicular germ cell neoplasia. J Reprod Immunol 100(2):135–145

    Google Scholar 

  • Ji C, Wang Y, Wang Y, Luan J, Yao L, Wang Y, Song N (2020) Immune-related genes play an important role in the prognosis of patients with testicular germ cell tumor. Ann Transl Med 8(14):866

    Google Scholar 

  • Jia Y, Kodumudi KN, Ramamoorthi G, Basu A, Snyder C, Wiener D, Pilon-Thomas S, Grover P, Zhang H, Greene MI, Mo Q, Tong Z, Chen Y-Z, Costa RLB, Han H, Lee C, Soliman H, Conejo-Garcia JR, Koski G, Czerniecki BJ (2021) Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway. Mol Therap 29(4):1541–1556

    Google Scholar 

  • Kalavska K, Sestakova Z, Mlcakova A, Kozics K, Gronesova P, Hurbanova L, Miskovska V, Rejlekova K, Svetlovska D, Sycova-Mila Z, Obertova J, Palacka P, Mardiak J, Chovanec M, Chovanec M, Mego M (2021) Are changes in the percentage of specific leukocyte subpopulations associated with endogenous DNA damage levels in testicular cancer patients? Int J Mol Sci 22(15)

    Google Scholar 

  • Kalavska K, Sestakova Z, Mlcakova A, Gronesova P, Miskovska V, Rejlekova K, Svetlovska D, Sycova-Mila Z, Obertova J, Palacka P, Mardiak J, Chovanec M, Chovanec M, Mego M (2022) Comprehensive assessment of selected immune cell subpopulations changes in chemotherapy-Naïve Germ cell tumor patients. Front Oncol 12:858797

    Google Scholar 

  • Kaur G, Thompson LA, Dufour JM (2014) Sertoli cells–immunological sentinels of spermatogenesis. Semin Cell Dev Biol 30:36–44

    Google Scholar 

  • Ke Z-B, Wu Y-P, Huang P, Hou J, Chen Y-H, Dong R-N, Lin F, Wei Y, Xue X-Y, Ng C-F, Xu N (2021) Identification of novel genes in testicular cancer microenvironment based on ESTIMATE algorithm-derived immune scores. J Cell Physiol 236(1):706–713

    Google Scholar 

  • Kim H-J, Cantor H (2014) CD4 T-cell subsets and tumor immunity: the helpful and the not-so-helpful. Cancer Immunol Res 2(2):91–98

    Google Scholar 

  • Kim SS, Sumner WA, Miyauchi S, Cohen EEW, Califano JA, Sharabi AB (2021) Role of B cells in responses to checkpoint blockade immunotherapy and overall survival of cancer patients. Clin Cancer Res 27(22):6075–6082

    Google Scholar 

  • Klein B, Haggeney T, Fietz D, Indumathy S, Loveland K, Hedger M, Kliesch S, Weidner W, Bergmann M, Schuppe HC (2016) Specific immune cell and cytokine characteristics of human testicular germ cell neoplasia. Hum Reprod. 31(10):2192–2202

    Google Scholar 

  • Klein B, Schuppe H-C, Bergmann M, Hedger MP, Loveland BE, Loveland KL (2017) An in vitro model demonstrates the potential of neoplastic human germ cells to influence the tumour microenvironment. Andrology 5(4):763–770

    Google Scholar 

  • Kliesch S, Schmidt S, Wilborn D, Aigner C, Albrecht W, Bedke J, Beintker M, Beyersdorff D, Bokemeyer C, Busch J, Classen J, de Wit M, Dieckmann K-P, Diemer T, Dieing A, Gockel M, Göckel-Beining B, Hakenberg OW, Heidenreich A, Heinzelbecker J, Herkommer K, Hermanns T, Kaufmann S, Kornmann M, Kotzerke J, Krege S, Kristiansen G, Lorch A, Müller A-C, Oechsle K, Ohloff T, Oing C, Otto U, Pfister D, Pichler R, Recken H, Rick O, Rudolph Y, Ruf C, Schirren J, Schmelz H, Schmidberger H, Schrader M, Schweyer S, Seeling S, Souchon R, Winter C, Wittekind C, Zengerling F, Zermann D-H, Zillmann R, Albers P (2021) Management of Germ Cell Tumours of the Testis in Adult Patients. German clinical practice guideline Part I: epidemiology, classification, diagnosis, prognosis, fertility preservation, and treatment recommendations for localized stages. Urol Int 105(3–4):169–180

    Google Scholar 

  • Knutson KL, Disis ML (2005) Tumor antigen-specific T helper cells in cancer immunity and immunotherapy. Cancer Immunol Immunother 54(8):721–728

    Google Scholar 

  • Kos K, Aslam MA, van de Ven R, Wellenstein MD, Pieters W, van Weverwijk A, Duits DEM, van Pul K, Hau C-S, Vrijland K, Kaldenbach D, Raeven EAM, Quezada SA, Beyaert R, Jacobs H, de Gruijl TD, de Visser KE (2022) Tumor-educated Tregs drive organ-specific metastasis in breast cancer by impairing NK cells in the lymph node niche. Cell Rep 38(9):110447

    Google Scholar 

  • Kunz DJ, Gomes T, James KR (2018) Immune cell dynamics unfolded by single-cell technologies. Front Immunol 9:1435

    Google Scholar 

  • Laguna M, Albers P, Algaba F, Brokemeyer C, Boormans J, di Nardo D, Fischer S, Fizazi K, Gremmels H, Leao R, Nicol D, Nicolai N, Oldenburg J, Tandstad T, Mayor de Castro J, Fankhauser C, Janisch F, Muilwijk T, Jain Y, Shepherd R (2022) EAU Guidelines on testicular cancer. In: EAU Guidelines Office (ed) EAU Guidelines. Arnhem, The Netherlands, pp 1–66

    Google Scholar 

  • Lee YS, Radford KJ (2019) The role of dendritic cells in cancer. Int Rev Cell Mol Biol 348:123–178

    Google Scholar 

  • Liu L, Cheng X, Yang H, Lian S, Jiang Y, Liang J, Chen X, Mo S, Shi Y, Zhao S, Li J, Jiang R, Yang D-H, Wu Y (2022a) BCL-2 expression promotes immunosuppression in chronic lymphocytic leukemia by enhancing regulatory T cell differentiation and cytotoxic T cell exhaustion. Mol Cancer 21(1):59

    Google Scholar 

  • Liu Y, Liu X, Xu Q, Gao X, Linghu E (2022b) A prognostic model of colon cancer based on the microenvironment component score via single cell sequencing. In Vivo 36(2):753–763

    Google Scholar 

  • Locati M, Mantovani A, Sica A (2013) Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 120:163–184

    Google Scholar 

  • Lokka E, Lintukorpi L, Cisneros-Montalvo S, Mäkelä J-A, Tyystjärvi S, Ojasalo V, Gerke H, Toppari J, Rantakari P, Salmi M (2020) Generation, localization and functions of macrophages during the development of testis. Nat Commun 11(1):4375

    Google Scholar 

  • Loveland KL, Klein B, Pueschl D, Indumathy S, Bergmann M, Loveland BE, Hedger MP, Schuppe H-C (2017) Cytokines in male fertility and reproductive pathologies: immunoregulation and beyond. Front Endocrinol 8:307

    Google Scholar 

  • Luckheeram RV, Zhou R, Verma AD, Xia B (2012) CD4+T cells: differentiation and functions. Clin Dev Immunol 2012:925135

    Google Scholar 

  • Lustig L, Guazzone VA, Theas MS, Pleuger C, Jacobo P, Pérez CV, Meinhardt A, Fijak M (2020) Pathomechanisms of autoimmune based testicular inflammation. Front Immunol 11:583135

    Google Scholar 

  • Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231���237

    Google Scholar 

  • Mateu-Jimenez M, Curull V, Pijuan L, Sánchez-Font A, Rivera-Ramos H, Rodríguez-Fuster A, Aguiló R, Gea J, Barreiro E (2017) Systemic and tumor Th1 and Th2 inflammatory profile and macrophages in lung cancer: influence of underlying chronic respiratory disease. J Thorac Oncol 12(2):235–248

    Google Scholar 

  • Mayer C, Adam M, Glashauser L, Dietrich K, Schwarzer JU, Köhn F-M, Strauss L, Welter H, Poutanen M, Mayerhofer A (2016) Sterile inflammation as a factor in human male infertility: involvement of Toll like receptor 2, biglycan and peritubular cells. Sci Rep 6:37128

    Google Scholar 

  • Mayerhofer A, Walenta L, Mayer C, Eubler K, Welter H (2018) Human testicular peritubular cells, mast cells and testicular inflammation. Andrologia 50(11):e13055

    Google Scholar 

  • McIver SC, Loveland KL, Roman SD, Nixon B, Kitazawa R, McLaughlin EA (2013) The chemokine CXCL12 and its receptor CXCR4 are implicated in human seminoma metastasis. Andrology 1(3):517–529

    Google Scholar 

  • McLachlan RI, Rajpert-De Meyts E, Hoei-Hansen CE, de Kretser DM, Skakkebaek NE (2007) Histological evaluation of the human testis–approaches to optimizing the clinical value of the assessment: mini review. Hum Reprod 22(1):2–16

    Google Scholar 

  • McMahon M, Ye S, Pedrina J, Dlugolenski D, Stambas J (2021) Extracellular matrix enzymes and immune cell biology. Front Mol Biosci 8:703868

    Google Scholar 

  • Melssen M, Slingluff CL (2017) Vaccines targeting helper T cells for cancer immunotherapy. Curr Opin Immunol 47:85–92

    Google Scholar 

  • Merad M, Sathe P, Helft J, Miller J, Mortha A (2013) The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31:563–604

    Google Scholar 

  • Mills CD (2015) Anatomy of a discovery: m1 and m2 macrophages. Front Immunol 6:212

    Google Scholar 

  • Moch H, Cubilla AL, Humphrey PA, Reuter VE, Ulbright TM (2016) The 2016 WHO classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 70(1):93–105

    Google Scholar 

  • Mossadegh-Keller N, Sieweke MH (2018) Testicular macrophages: guardians of fertility. Cell Immunol 330:120–125

    Google Scholar 

  • Mousset CM, Hobo W, Woestenenk R, Preijers F, Dolstra H, van der Waart AB (2019) Comprehensive phenotyping of T cells using flow cytometry. Cytometry A 95(6):647–654

    Google Scholar 

  • Nakanoma T, Nakamura K, Deguchi N, Fujimoto J, Tazaki H, Hata J (1992) Immunohistological analysis of tumour infiltrating lymphocytes in seminoma using monoclonal antibodies. Virchows Arch A Pathol Anat Histopathol 421(5):409–413

    Google Scholar 

  • Nestler T, Dalvi P, Haidl F, Wittersheim M, von Brandenstein M, Paffenholz P, Wagener-Ryczek S, Pfister D, Koitzsch U, Hellmich M, Buettner R, Odenthal M, Heidenreich A (2022) Transcriptome analysis reveals upregulation of immune response pathways at the invasive tumour front of metastatic seminoma germ cell tumours. Br J Cancer 126(6):937–947

    Google Scholar 

  • Nouri AME, Hussain RF, Oliver RTD, Handy AM, Bartkova I, Bodmer JG (1993) Immunological paradox in testicular tumours: the presence of a large number of activated T-cells despite the complete absence of MHC antigens. Eur J Cancer 29(13):1895–1899

    Google Scholar 

  • O’Donnell L, Rebourcet D, Dagley LF, Sgaier R, Infusini G, O’Shaughnessy PJ, Chalmel F, Fietz D, Weidner W, Legrand JMD, Hobbs RM, McLachlan RI, Webb AI, Pilatz A, Diemer T, Smith LB, Stanton PG (2021) Sperm proteins and cancer-testis antigens are released by the seminiferous tubules in mice and men. FASEB J 35(3):e21397

    Google Scholar 

  • Ockhuizen T, Pandey JP, Marrink J, Fudenberg HH (1982) Immunoglobulin allotypes and nonseminoma testicular cancer. Oncology 39(3):152–155

    Google Scholar 

  • Page A, Hubert J, Fusil F, Cosset F-L (2021) Exploiting B cell transfer for cancer therapy: engineered B cells to eradicate tumors. Int J Mol Sci 22(18):9991. https://pubmed.ncbi.nlm.nih.gov/34576154/

  • Paijens ST, Vledder A, de Bruyn M, Nijman HW (2021) Tumor-infiltrating lymphocytes in the immunotherapy era. Cell Mol Immunol 18(4):842–859

    Google Scholar 

  • Pan Y, Yu Y, Wang X, Zhang T (2020) Tumor-associated macrophages in tumor immunity. Front Immunol 11:583084

    Google Scholar 

  • Parker C, Milosevic M, Panzarella T, Banerjee D, Jewett M, Catton C, Tew-George B, Gospodarowicz M, Warde P (2002) The prognostic significance of the tumour infiltrating lymphocyte count in stage I testicular seminoma managed by surveillance. Eur J Cancer 38(15):2014–2019

    Google Scholar 

  • Payne K, Li W, Salomon R, Ma CS (2020) OMIP-063: 28-color flow cytometry panel for broad human Immunophenotyping. Cytometry A 97(8):777–781

    Google Scholar 

  • Pearce H, Hutton P, Chaudhri S, Porfiri E, Patel P, Viney R, Moss P (2017) Spontaneous CD4+ and CD8+ T-cell responses directed against cancer testis antigens are present in the peripheral blood of testicular cancer patients. Eur J Immunol 47(7):1232–1242

    Google Scholar 

  • Pelletier R-M (2011) The blood-testis barrier: the junctional permeability, the proteins and the lipids. Prog Histochem Cytochem 46(2):49–127

    Google Scholar 

  • Pollari M, Brück O, Pellinen T, Vähämurto P, Karjalainen-Lindsberg M-L, Mannisto S, Kallioniemi O, Kellokumpu-Lehtinen P-L, Mustjoki S, Leivonen S-K, Leppä S (2018) PD-L1+ tumor-associated macrophages and PD-1+ tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma. Haematologica 103(11):1908–1914

    Google Scholar 

  • Pomajzl AJ, Siref LE (2021) Leydig cell cancer. StatPearls, Treasure Island

    Google Scholar 

  • Ponte R, Dupuy FP, Brimo F, Mehraj V, Brassard P, Belanger M, Yurchenko E, Jenabian M-A, Bernard NF, Routy J-P (2018) Characterization of myeloid cell populations in human testes collected after sex reassignment surgery. J Reprod Immunol 125:16–24

    Google Scholar 

  • Qin Y, Peng F, Ai L, Mu S, Li Y, Yang C, Hu Y (2021) Tumor-infiltrating B cells as a favorable prognostic biomarker in breast cancer: a systematic review and meta-analysis. Cancer Cell Int 21(1):310

    Google Scholar 

  • Rajpert-De Meyts E, Nielsen JE, Skakkebaek NE, Almstrup K (2015) Diagnostic markers for germ cell neoplasms: from placental-like alkaline phosphatase to micro-RNAs. Folia Histochem Cytobiol 53(3):177–188. https://pubmed.ncbi.nlm.nih.gov/26306513/

    Google Scholar 

  • Rajpert-De Meyts E, McGlynn KA, Okamoto K, Jewett MAS, Bokemeyer C (2016) Testicular germ cell tumours. Lancet 387(10029):1762–1774

    Google Scholar 

  • Raspollini MR (2014) Histologic variants of seminoma mimicking lymphatic malignancies of the testis: a literature review with a report of case series focusing on problems in differential diagnosis. Appl Immunohistochem Mol Morphol 22(5):348–357

    Google Scholar 

  • Rodgers CB, Mustard CJ, McLean RT, Hutchison S, Pritchard AL (2022) A B-cell or a key player? The different roles of B-cells and antibodies in melanoma. Pigment Cell Melanoma Res 35(3):303–319

    Google Scholar 

  • Rosser EC, Mauri C (2021) The emerging field of regulatory B cell immunometabolism. Cell Metab 33(6):1088–1097

    Google Scholar 

  • Sadigh S, Farahani SJ, Shah A, Vaughn D, Lal P (2020) Differences in PD-L1-expressing macrophages and immune microenvironment in testicular germ cell tumors. Am J Clin Pathol 153(3):387–395

    Google Scholar 

  • Sakai Y, Hoshino H, Kitazawa R, Kobayashi M (2014) High endothelial venule-like vessels and lymphocyte recruitment in testicular seminoma. Andrology 2(2):282–289

    Google Scholar 

  • Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen Y-T, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543

    Google Scholar 

  • Schreiber RD, Old LJ, Smyth MJ (2011) Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331(6024):1565–1570

    Google Scholar 

  • Schütte B, Holstein AF, Schirren C (1988) Macrophages lysing seminoma cells in patients with carcinoma-in-situ (CIS) of the testis. Andrologia 20(4):295–303

    Google Scholar 

  • Sharpe RM, McKinnell C, Kivlin C, Fisher JS (2003) Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood. Reproduction 125(6):769–784

    Google Scholar 

  • Sims D, Sudbery I, Ilott NE, Heger A, Ponting CP (2014) Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet 15(2):121–132

    Google Scholar 

  • Siska PJ, Johnpulle RAN, Zhou A, Bordeaux J, Kim JY, Dabbas B, Dakappagari N, Rathmell JC, Rathmell WK, Morgans AK, Balko JM, Johnson DB (2017) Deep exploration of the immune infiltrate and outcome prediction in testicular cancer by quantitative multiplexed immunohistochemistry and gene expression profiling. Onco Targets Ther 6(4):e1305535

    Google Scholar 

  • Skakkebaek NE (1972) Possible carcinoma-in-situ of the testis. Lancet 2(7776):516–517

    Google Scholar 

  • Skakkebaek NE, Rajpert-De Meyts E, Buck Louis GM, Toppari J, Andersson A-M, Eisenberg ML, Jensen TK, Jørgensen N, Swan SH, Sapra KJ, Ziebe S, Priskorn L, Juul A (2016) Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol Rev 96(1):55–97

    Google Scholar 

  • Song Y, Qi X, Kang J, Wang X, Ou N, Zhu J, Wang S, Liu X (2021) Identification of new biomarkers in immune microenvironment of testicular germ cell tumour. Andrologia 53(3):e13986

    Google Scholar 

  • Szarek M, Bergmann M, Konrad L, Schuppe H-C, Kliesch S, Hedger MP, Loveland KL (2019) Activin a target genes are differentially expressed between normal and neoplastic adult human testes: clues to gonocyte fate choice. Andrology 7(1):31–41

    Google Scholar 

  • Torres A, Casanova JF, Nistal M, Regadera J (1997) Quantification of immunocompetent cells in testicular germ cell tumours. Histopathology 30(1):23–30

    Google Scholar 

  • Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman W-H, Pagès F, Galon J (2011) Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 71(4):1263–1271

    Google Scholar 

  • Tsai M-J, Chang W-A, Huang M-S, Kuo P-L (2014) Tumor microenvironment. A new treatment target for cancer. ISRN Biochem 2014:351959

    Google Scholar 

  • Tung KSK, Harakal J, Qiao H, Rival C, Li JCH, Paul AGA, Wheeler K, Pramoonjago P, Grafer CM, Sun W, Sampson RD, Wong EWP, Reddi PP, Deshmukh US, Hardy DM, Tang H, Cheng CY, Goldberg E (2017) Egress of sperm autoantigen from seminiferous tubules maintains systemic tolerance. J Clin Invest 127(3):1046–1060

    Google Scholar 

  • Tveita AA, Schjesvold F, Haabeth OA, Fauskanger M, Bogen B (2015) Tumors escape CD4+ T-cell-mediated immunosurveillance by impairing the ability of infiltrating macrophages to indirectly present tumor antigens. Cancer Res 75(16):3268–3278

    Google Scholar 

  • Walker JA, McKenzie ANJ (2018) TH2 cell development and function. Nat Rev Immunol 18(2):121–133

    Google Scholar 

  • Wang M, Fijak M, Hossain H, Markmann M, Nüsing RM, Lochnit G, Hartmann MF, Wudy SA, Zhang L, Gu H, Konrad L, Chakraborty T, Meinhardt A, Bhushan S (2017) Characterization of the micro-environment of the testis that shapes the phenotype and function of testicular macrophages. J Immunol (Baltimore, MD: 1950) 198(11):4327–4340

    Google Scholar 

  • Wang M, Yang Y, Cansever D, Wang Y, Kantores C, Messiaen S, Moison D, Livera G, Chakarov S, Weinberger T, Stremmel C, Fijak M, Klein B, Pleuger C, Lian Z, Ma W, Liu Q, Klee K, Händler K, Ulas T, Schlitzer A, Schultze JL, Becher B, Greter M, Liu Z, Ginhoux F, Epelman S, Schulz C, Meinhardt A, Bhushan S (2021) Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis. Proc Natl Acad Sci U S A 118(1):e2013686117. https://pubmed.ncbi.nlm.nih.gov/33372158/

  • Wei Y, Huang C-X, Xiao X, Chen D-P, Shan H, He H, Kuang D-M (2021) B cell heterogeneity, plasticity, and functional diversity in cancer microenvironments. Oncogene 40(29):4737–4745

    Google Scholar 

  • Willis SN, Mallozzi SS, Rodig SJ, Cronk KM, McArdel SL, Caron T, Pinkus GS, Lovato L, Shampain KL, Anderson DE, Anderson RCE, Bruce JN, O’Connor KC (2009) The microenvironment of germ cell tumors harbors a prominent antigen-driven humoral response. J Immunol (Baltimore, MD: 1950) 182(5):3310–3317

    Google Scholar 

  • Windschüttl S, Nettersheim D, Schlatt S, Huber A, Welter H, Schwarzer JU, Köhn FM, Schorle H, Mayerhofer A (2014) Are testicular mast cells involved in the regulation of germ cells in man? Andrology 2(4):615–622

    Google Scholar 

  • Wu H, Zhang Z, Xiao X-Y, Zhang Z-Y, Gao S-L, Lu C, Zuo L, Zhang L-F (2021) Toll-like receptor 2 (TLR2) is a candidate prognostic factor in testicular germ cell tumors as well as an indicator of immune function in the tumor microenvironment. Bioengineered 12(1):1939–1951

    Google Scholar 

  • Yakirevich E, Lefel O, Sova Y, Stein A, Cohen O, Izhak OB, Resnick MB (2002) Activated status of tumour-infiltrating lymphocytes and apoptosis in testicular seminoma. J Pathol 196(1):67–75

    Google Scholar 

  • Yang Q, Cheng C, Zhu R, Guo F, Lai R, Liu X, Li M (2022a) A N6-methyladenosine-related long noncoding RNAs model for predicting prognosis in oral squamous cell carcinoma: association with immune cell infiltration and tumor metastasis. Oral Oncol 127:105771

    Google Scholar 

  • Yang Y, Yang X, Wang Y, Xu J, Shen H, Gou H, Qin X, Jiang G (2022b) Combined consideration of tumor-associated immune cell density and immune checkpoint expression in the Peritumoral microenvironment for prognostic stratification of non-small-cell lung cancer patients. Front Immunol 13:811007

    Google Scholar 

  • Zhang L, Zhang Z (2019) Recharacterizing tumor-infiltrating lymphocytes by single-cell RNA sequencing. Cancer Immunol Res 7(7):1040–1046

    Google Scholar 

  • Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (2003) Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348(3):203–213

    Google Scholar 

  • Zhang Y, Hou F, Liu X, Ma D, Zhang Y, Kong B, Cui B (2014) Tc17 cells in patients with uterine cervical cancer. PLoS One 9(2):e86812

    Google Scholar 

  • Zhao S, Zhu W, Xue S, Han D (2014) Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol 11(5):428–437

    Google Scholar 

  • Zheng W, Chen J, Liu C, Zhou J, Zhu C, Fan Y, Duan Y, Li X (2016) Immature CD11c+ myeloid dendritic cells with inflammatory and regulatory cytokine profile in human seminoma. Int J Clin Exp Pathol 9(3):2803–2819

    Google Scholar 

  • Zheng X, Weigert A, Reu S, Guenther S, Mansouri S, Bassaly B, Gattenlöhner S, Grimminger F, Pullamsetti S, Seeger W, Winter H, Savai R (2020) Spatial density and distribution of tumor-associated macrophages predict survival in non-small cell lung carcinoma. Cancer Res 80(20):4414–4425

    Google Scholar 

  • Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Veterinary Anatomy, Histology and Embryology, Justus Liebig University Giessen, Giessen, Germany

    Daniela Fietz

  2. Andrology Unit, Department of Urology, Pediatric Urology and Andrology, Justus Liebig University Giessen, Giessen, Germany

    Hans-Christian Schuppe

  3. Centre for Reproductive Health, Hudson Institute for Medical Research, Clayton, VIC, Australia

    Katherine L. Loveland

  4. Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia

    Katherine L. Loveland

Authors
  1. Daniela Fietz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hans-Christian Schuppe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine L. Loveland
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniela Fietz .

Ethics declarations

The authors declare that there is no conflict of interest.

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Fietz, D., Schuppe, HC., Loveland, K.L. (2022). Immunobiology of Testicular Cancer. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2022_7

Download citation

  • DOI: https://doi.org/10.1007/16833_2022_7

  • Published:

  • Publisher Name: Springer, Cham

Publish with us

Policies and ethics

Search

Navigation