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FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice

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Abstract

Tumors evade immune recognition and destruction in many ways including the creation of an immune-suppressive tumor microenvironment (TME). Dendritic cells (DC) that infiltrate the TME are tolerogenic, and suppress effector T cells and anti-tumor activity. Previous reports demonstrated that a key regulator of tolerance in DC is the transcription factor FOXO3. Gender disparity has been studied in cancer in relation to incidence, aggressiveness, and prognosis. Few studies have touched on the importance in relation to impact on the immune system. In the current study, we show that there are significant differences in tumor growth between males and females. Additionally, frequencies and the function of FOXO3 expressed by DC subsets that infiltrate tumors vary between genders. Our results show for the first time that DC FOXO3 expression and function is altered in females. In vitro results indicate that these differences may be the result of exposure to estrogen. These differences may be critical considerations for the enhancement of immunotherapy for cancer.

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Abbreviations

AR:

Androgen receptor

BMDC:

Bone marrow-derived DC

ChIP:

Chromatin immunoprecipitation

DHT:

Dihydrotestosterone

E2:

17-β-estradiol,

ERα:

Estrogen receptor alpha

ERβ:

Estrogen receptor beta

HCC:

Hepatocellular carcinoma

Het:

Heterozygous

MDSC:

Myeloid-derived suppressor cell(s)

pDC:

Plasmacytoid DC

TADC:

Tumor-associated dendritic cell(s)

Tfm:

Testicular feminized mouse

TME:

Tumor microenvironment,

Treg:

T regulatory cell(s)

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Acknowledgements

The authors would like to thank Dr. Michael Nishimura for research oversight and manuscript preparation. We would also like to thank Dr. Jose Guevara-Patino for his critical review and discussions during manuscript preparation.

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Authors and Affiliations

  1. Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave. Building 112, Maywood, IL, 60153, USA

    Matthew G. Thompson, Daniel S. Peiffer, Michelle Larson, Flor Navarro & Stephanie K. Watkins

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  1. Matthew G. Thompson
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  2. Daniel S. Peiffer
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  4. Flor Navarro
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Correspondence to Stephanie K. Watkins.

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Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R00CA151294. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was further supported by Loyola University Chicago start-up funds.

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Thompson, M.G., Peiffer, D.S., Larson, M. et al. FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice. Cancer Immunol Immunother 66, 615–625 (2017). https://doi.org/10.1007/s00262-017-1972-4

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  • DOI: https://doi.org/10.1007/s00262-017-1972-4

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