FOXO3, Estrogen Receptor Alpha, and Androgen Receptor Impact Tumor Growth Rate and Infiltration of Dendritic Cell Subsets Differentially Between Male and Female Mice

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2017 Feb 24

PMID 28229217

Citations 16

Authors

Matthew G Thompson

Daniel S Peiffer

Michelle Larson

Flor Navarro

Stephanie K Watkins

Affiliations

Soon will be listed here.

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.

Citing Articles

The Estrogen-Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection.

Zhao Y, Klionsky D, Wang X, Huang Q, Deng Z, Xiang J Int J Mol Sci. 2024; 25(23).

PMID: 39684286 PMC: 11641569. DOI: 10.3390/ijms252312576.

Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications.

Shi Y, Shi M, Wang Y, You J Signal Transduct Target Ther. 2024; 9(1):322.

PMID: 39543114 PMC: 11564800. DOI: 10.1038/s41392-024-02002-z.

An Insight into Perfusion Anisotropy within Solid Murine Lung Cancer Tumors.

Martino A, Terracciano R, Milicevic B, Milosevic M, Simic V, Fallon B Pharmaceutics. 2024; 16(8).

PMID: 39204354 PMC: 11360231. DOI: 10.3390/pharmaceutics16081009.

Evidence-Based Severity Assessment of Animal Models for Pancreatic Cancer.

Schreiber T, Koopmann I, Brandstetter J, Talbot S, Goldstein L, Hoffmann L Biomedicines. 2024; 12(7).

PMID: 39062067 PMC: 11275077. DOI: 10.3390/biomedicines12071494.

Sex differences in cancer and immunotherapy outcomes: the role of androgen receptor.

Zhao J, Wang Q, Tan A, Loh C, Toh H Front Immunol. 2024; 15:1416941.

PMID: 38863718 PMC: 11165033. DOI: 10.3389/fimmu.2024.1416941.

References

Suzuki T, Miki Y, Nakamura Y, Moriya T, Ito K, Ohuchi N . Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer. 2005; 12(4):701-20. DOI: 10.1677/erc.1.00834. View

Thompson M, Larson M, Vidrine A, Barrios K, Navarro F, Meyers K . FOXO3-NF-κB RelA Protein Complexes Reduce Proinflammatory Cell Signaling and Function. J Immunol. 2015; 195(12):5637-47. PMC: 4670825. DOI: 10.4049/jimmunol.1501758. View

Papenfuss T, Powell N, McClain M, Bedarf A, Singh A, Gienapp I . Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J Immunol. 2011; 186(6):3346-55. PMC: 3600583. DOI: 10.4049/jimmunol.1001322. View

Che Q, Liu B, Liao Y, Zhang H, Yang T, He Y . Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17β-estradiol biosynthesis in endometrial carcinoma microenvironment. Int J Cancer. 2013; 135(2):282-94. DOI: 10.1002/ijc.28679. View

Klein S, Marriott I, Fish E . Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg. 2015; 109(1):9-15. PMC: 4447843. DOI: 10.1093/trstmh/tru167. View

Paharkova-Vatchkova V, Maldonado R, Kovats S . Estrogen preferentially promotes the differentiation of CD11c+ CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol. 2004; 172(3):1426-36. DOI: 10.4049/jimmunol.172.3.1426. View

Lin P, Sun L, Thibodeaux S, Ludwig S, Vadlamudi R, Hurez V . B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol. 2010; 185(5):2747-53. PMC: 3244840. DOI: 10.4049/jimmunol.1000496. View

Wichmann M, Ayala A, Chaudry I . Male sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage. Am J Physiol. 1997; 273(4):C1335-40. DOI: 10.1152/ajpcell.1997.273.4.C1335. View

Yang L, Xie S, Jamaluddin M, Altuwaijri S, Ni J, Kim E . Induction of androgen receptor expression by phosphatidylinositol 3-kinase/Akt downstream substrate, FOXO3a, and their roles in apoptosis of LNCaP prostate cancer cells. J Biol Chem. 2005; 280(39):33558-65. DOI: 10.1074/jbc.M504461200. View

10.

Munn D . Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2011; 4(2):734-45. DOI: 10.2741/e414. View

11.

Straub R . The complex role of estrogens in inflammation. Endocr Rev. 2007; 28(5):521-74. DOI: 10.1210/er.2007-0001. View

12.

Olsen N, Olson G, Viselli S, Gu X, Kovacs W . Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology. 2001; 142(3):1278-83. DOI: 10.1210/endo.142.3.8032. View

13.

Salem M . Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004; 3(1):97-104. DOI: 10.2174/1568010043483944. View

14.

Krementsov D, Noubade R, Dragon J, Otsu K, Rincon M, Teuscher C . Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol. 2013; 75(1):50-66. PMC: 3945470. DOI: 10.1002/ana.24020. View

15.

Yakimchuk K, Jondal M, Okret S . Estrogen receptor α and β in the normal immune system and in lymphoid malignancies. Mol Cell Endocrinol. 2013; 375(1-2):121-9. DOI: 10.1016/j.mce.2013.05.016. View

16.

Lai J, Lai K, Chuang K, Chang P, Yu I, Lin W . Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Invest. 2009; 119(12):3739-51. PMC: 2786793. DOI: 10.1172/JCI39335. View

17.

Roden A, Moser M, Tri S, Mercader M, Kuntz S, Dong H . Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol. 2004; 173(10):6098-108. DOI: 10.4049/jimmunol.173.10.6098. View

18.

McCombe P, Greer J, Mackay I . Sexual dimorphism in autoimmune disease. Curr Mol Med. 2009; 9(9):1058-79. DOI: 10.2174/156652409789839116. View

19.

Yeh S, Chen P . Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Oncology. 2010; 78 Suppl 1:172-9. DOI: 10.1159/000315247. View

20.

Lai J, Lai K, Zeng W, Chuang K, Altuwaijri S, Chang C . Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: lessons from conditional AR knockout mice. Am J Pathol. 2012; 181(5):1504-12. PMC: 3483803. DOI: 10.1016/j.ajpath.2012.07.008. View