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01-05-2017 | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 5/2017

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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Cutolo M, Sulli A, Straub RH (2014) Estrogen’s effects in chronic autoimmune/inflammatory diseases and progression to cancer. Expert Rev Clin Immunol 10(1):31–39. doi:10.1586/1744666x.2014.863149 CrossRefPubMed

Hwang TL, Chen CY (2012) Gender different response to immunonutrition in liver cirrhosis with sepsis in rats. Nutrients 4(3):231–242. doi:10.3390/nu4030231 CrossRefPubMedPubMedCentral

Klein SL, Marriott I, Fish EN (2015) Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg 109(1):9–15. doi:10.1093/trstmh/tru167 CrossRefPubMedPubMedCentral

Krementsov DN, Noubade R, Dragon JA, Otsu K, Rincon M, Teuscher C (2014) Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol 75(1):50–66. doi:10.1002/ana.24020 CrossRefPubMedPubMedCentral

McCombe PA, Greer JM, Mackay IR (2009) Sexual dimorphism in autoimmune disease. Curr Mol Med 9(9):1058–1079CrossRefPubMed

Nhamoyebonde S, Leslie A (2014) Biological differences between the sexes and susceptibility to tuberculosis. J Infect Dis 209(Suppl 3):S100–S106. doi:10.1093/infdis/jiu147 CrossRefPubMed

van Lunzen J, Altfeld M (2014) Sex differences in infectious diseases-common but neglected. J Infect Dis 209(Suppl 3):S79–S80. doi:10.1093/infdis/jiu159 CrossRefPubMed

Yeh SH, Chen PJ (2010) Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Int Soc Cell 78(Suppl 1):172–179. doi:10.1159/000315247

Wichmann MW, Ayala A, Chaudry IH (1997) Male sex steroids are responsible for depressing macrophage immune function after trauma-hemorrhage. Am J Physiol 273(4 Pt 1):C1335–C1340PubMed

10.

Gilliver SC, Ashworth JJ, Mills SJ, Hardman MJ, Ashcroft GS (2006) Androgens modulate the inflammatory response during acute wound healing. J Cell Sci 119 (Pt 4):722–732. doi:10.1242/jcs.02786 PubMed

11.

Olsen NJ, Olson G, Viselli SM, Gu X, Kovacs WJ (2001) Androgen receptors in thymic epithelium modulate thymus size and thymocyte development. Endocrinology 142(3):1278–1283. doi:10.1210/endo.142.3.8032 PubMed

12.

Roden AC, Moser MT, Tri SD, Mercader M, Kuntz SM, Dong H, Hurwitz AA, McKean DJ, Celis E, Leibovich BC, Allison JP, Kwon ED (2004) Augmentation of T cell levels and responses induced by androgen deprivation. J Immunol 173(10):6098–6108CrossRefPubMed

13.

Lai JJ, Lai KP, Zeng W, Chuang KH, Altuwaijri S, Chang C (2012) Androgen receptor influences on body defense system via modulation of innate and adaptive immune systems: lessons from conditional AR knockout mice. Am J Pathol 181(5):1504–1512. doi:10.1016/j.ajpath.2012.07.008 CrossRefPubMedPubMedCentral

14.

Sachdeva M, Mo YY (2010) Stroma-mediated expression of estrogen and its role in cancer. Front Biosci 15:237–248CrossRef

15.

Che Q, Liu BY, Liao Y, Zhang HJ, Yang TT, He YY, Xia YH, Lu W, He XY, Chen Z, Wang FY, Wan XP (2014) Activation of a positive feedback loop involving IL-6 and aromatase promotes intratumoral 17beta-estradiol biosynthesis in endometrial carcinoma microenvironment. Int J Cancer 135(2):282–294. doi:10.1002/ijc.28679 CrossRefPubMed

16.

Suzuki T, Miki Y, Nakamura Y, Moriya T, Ito K, Ohuchi N, Sasano H (2005) Sex steroid-producing enzymes in human breast cancer. Endocr Relat Cancer 12(4):701–720. doi:10.1677/erc.1.00834 CrossRefPubMed

17.

Chuang KH, Altuwaijri S, Li G, Lai JJ, Chu CY, Lai KP, Lin HY, Hsu JW, Keng P, Wu MC, Chang C (2009) Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor. J Exp Med 206(5):1181–1199. doi:10.1084/jem.20082521 CrossRefPubMedPubMedCentral

18.

Lai JJ, Lai KP, Chuang KH, Chang P, Yu IC, Lin WJ, Chang C (2009) Monocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Investig 119(12):3739–3751. doi:10.1172/JCI39335 CrossRefPubMedPubMedCentral

19.

Straub RH (2007) The complex role of estrogens in inflammation. Endocr Rev 28(5):521–574. doi:10.1210/er.2007-0001 CrossRefPubMed

20.

Paharkova-Vatchkova V, Maldonado R, Kovats S (2004) Estrogen preferentially promotes the differentiation of CD11c + CD11b(intermediate) dendritic cells from bone marrow precursors. J Immunol 172(3):1426–1436CrossRefPubMed

21.

Papenfuss TL, Powell ND, McClain MA, Bedarf A, Singh A, Gienapp IE, Shawler T, Whitacre CC (2011) Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J Immunol 186(6):3346–3355. doi:10.4049/jimmunol.1001322 CrossRefPubMedPubMedCentral

22.

Dejean AS, Beisner DR, Ch’en IL, Kerdiles YM, Babour A, Arden KC, Castrillon DH, DePinho RA, Hedrick SM (2009) Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat Immunol 10(5):504–513. doi:10.1038/ni.1729 CrossRefPubMedPubMedCentral

23.

Thompson MG, Larson M, Vidrine A, Barrios K, Navarro F, Meyers K, Simms P, Prajapati K, Chitsike L, Hellman LM, Baker BM, Watkins SK (2015) FOXO3-NF-kappaB RelA protein complexes reduce proinflammatory cell signaling and function. J Immunol 195(12):5637–5647. doi:10.4049/jimmunol.1501758 CrossRefPubMedPubMedCentral

24.

Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH (2011) Coactivation of AKT and beta-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res 71(7):2718–2727. doi:10.1158/0008-5472.can-10-2705 CrossRefPubMedPubMedCentral

25.

Salem ML (2004) 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 3(1):97–104CrossRefPubMed

26.

Yakimchuk K, Jondal M, Okret S (2013) Estrogen receptor alpha and beta in the normal immune system and in lymphoid malignancies. Mol Cell Endocrinol 375 (1–2):121–129. doi:10.1016/j.mce.2013.05.016 CrossRefPubMed

27.

Rutella S, Danese S, Leone G (2006) Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108(5):1435–1440. doi:10.1182/blood-2006-03-006403 CrossRefPubMed

28.

Guo S, Sonenshein GE (2004) Forkhead box transcription factor FOXO3a regulates estrogen receptor alpha expression and is repressed by the Her-2/neu/phosphatidylinositol 3-kinase/Akt signaling pathway. Mol Cell Biol 24(19):8681–8690. doi:10.1128/MCB.24.19.8681-8690.2004 CrossRefPubMedPubMedCentral

29.

Yang L, Xie S, Jamaluddin MS, Altuwaijri S, Ni J, Kim E, Chen YT, Hu YC, Wang L, Chuang KH, Wu CT, Chang C (2005) 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 280(39):33558–33565. doi:10.1074/jbc.M504461200 CrossRefPubMed

30.

Lin PY, Sun L, Thibodeaux SR, Ludwig SM, Vadlamudi RK, Hurez VJ, Bahar R, Kious MJ, Livi CB, Wall SR, Chen L, Zhang B, Shin T, Curiel TJ (2010) B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol 185(5):2747–2753. doi:10.4049/jimmunol.1000496 CrossRefPubMedPubMedCentral

31.

Munn DH (2012) Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed) 4:734–745CrossRef

32.

Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, Sun LZ (2015) Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells. PLoS ONE 10(4):e0121136. doi:10.1371/journal.pone.0121136 CrossRefPubMedPubMedCentral

Title: FOXO3, estrogen receptor alpha, and androgen receptor impact tumor growth rate and infiltration of dendritic cell subsets differentially between male and female mice
Authors: Matthew G. Thompson
Daniel S. Peiffer
Michelle Larson
Flor Navarro
Stephanie K. Watkins
Publication date: 01-05-2017
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 5/2017
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-017-1972-4

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