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NK cell-mediated antibody-dependent cellular cytotoxicity is enhanced by tamoxifen in HER2/neu non-amplified, but not HER2/neu-amplified, breast cancer cells

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

An Erratum to this article was published on 01 October 2016

Abstract

Tumor-targeting antibodies have been successful in the treatment of various types of cancers. Antibodies engage the immune system with their Fc, stimulating immune cell effector function. In the clinic, FcγRIIIa polymorphisms with higher affinity for the Fc of antibodies were shown to improve response rates and overall survival. Efforts have been made to modify the Fc to enhance affinity to Fc receptors and thereby improve effector function. An alternative for improving immune effector function may be to increase the level of tumor antigen expression. In this study, tamoxifen was used to increase HER2/neu protein level to determine whether increased tumor antigen expression could enhance NK cell-mediated antibody-dependent cytotoxicity (ADCC). Tamoxifen was found to increase HER2/neu 1.5-fold to threefold in breast cancer cell lines that were HER2/neu non-amplified. Using flow cytometry to simultaneously evaluate NK cell degranulation and tumor cell death, the increase in HER2/neu enhanced NK cell-mediated ADCC. However, in cells that had HER2/neu gene amplification and estrogen receptor expression, tamoxifen elevated HER2/neu but failed to improve NK cell function. The quantity of HER2/neu on the tumor cell surface was approximately double that of the number of Fc receptors found on NK cells. This appears to reflect a ceiling at which increasing antigen expression fails to improve NK cell effector function. This has clinical implications as trying to increase antigen expression to enhance NK cell function may be useful for patients with antigen-low tumors, but not in those whose tumors have gene amplification or high levels of antigen expression.

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Abbreviations

ABC:

Antibody binding capacity

ADCC:

Antibody-dependent cellular cytotoxicity

CFSE:

Carboxyfluorescein succinimidyl ester

ER:

Estrogen receptor

FSC:

Forward scatter

IgG:

Immunoglobulin gamma

PAX2:

Paired box 2

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

SSC:

Side scatter

4OHT:

4-hydroxytamoxifen

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Acknowledgments

This research was supported by an Aurora Cancer Care Research Award (Grant #505/3979) and internal funds. We would like to thank Joe Grundle and Katie Klein for assistance with editing and figures.

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Authors and Affiliations

  1. Immunotherapy Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Health Care, Milwaukee, WI, USA

    John O. Richards, Alex J. Albers & Thomas S. Smith

  2. Aurora Research Institute, Aurora Health Care, Milwaukee, WI, USA

    John O. Richards, Alex J. Albers, Thomas S. Smith & Judy A. Tjoe

  3. Surgical Breast Oncology, Aurora Cancer Care, Aurora Health Care, Milwaukee, WI, USA

    Judy A. Tjoe

  4. Immunology Research Laboratory, Aurora Research Institute, 960 N. 12th Street, 3rd Floor, Milwaukee, WI, 53233, USA

    John O. Richards

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Correspondence to John O. Richards.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00262-016-1903-9.

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Richards, J.O., Albers, A.J., Smith, T.S. et al. 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). https://doi.org/10.1007/s00262-016-1885-7

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