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AIBCCR 2022: The Implications of Biological Sex in Bladder Cancer

Session: Sex as a Biological Variable in Bladder Cancer

The afternoon session started with Dr. Ingersoll (Institut Pasteur) discussing sex in bladder cancer. She started by explaining the difference between sex and gender. Sex is dependent on chromosome organization, sex steroids levels, reproductive organs, and sexually dimorphic characteristics. Gender is a social construct and related to behaviors. Sex differences are responsible for the difference in bladder cancer incidence while gender related differences are observed because of differences in smoking and bladder cancer occupational risk factors. Drivers of sex bias in bladder cancer are likely related to sex chromosomes in terms of genetic and epigenetic differences and sex hormones and their downstream receptors such as ERα, ERβ, GPER1, and androgen receptor (AR). In her research, she reported no difference in immune cells infiltration between sexes except for tumor specific T cells. She concluded by citing a study of 1000 healthy individuals where they evaluated the effects of sex on transcriptional responses of most immune-related genes using microbial challenges.1 They noted sex differences in gene expression of CD4+T cells and monocytes.

During the second talk, Dr. Miyamoto (University of Rochester) provided an overview of the molecular biology of sex hormone receptors in bladder cancer. Specifically, he discussed the role of AR in tumorgenicity, progression and response to conventional chemotherapy and immunotherapy. In a mice model study, 92% of the male wild-type AR mice developed bladder cancer while 50% of castrated male wild-type mice developed cancer. In comparison, 42% of the wild-type female mice developed cancer and none of the female AR knock out mice developed cancer. Overall, there was a trend of AR activity down regulating tumor suppressors such as UGT1A1 and upregulating oncogenic molecules such as NFKB in non-neoplastic urothelial cells. AR pathway targets within bladder cancer cells include EGFR, AKT, WNT, ELK, NFKB, ATF2, and FOXO1. Finally, in terms of therapeutic resistance, he noted decreased BCG therapy efficacy via modulation of Rab27b induced exocytosis in AR+ cancers. Furthermore, AR positive cells were more resistant to cisplatin chemotherapy and radiation therapy.2 In the estrogen domain, he discussed the potential outcome of having ER+ tumors depending on subunit of the estrogen receptor present; with ERα likely protective and ERβ likely oncogenic.3

The role of sex chromosomes and sex hormones were presented by Dr. Sean Li (Boston Children’s Hospital and Harvard Medical School). Utilizing four different sex genotypes in his lab including XYM, XYF, XXM and XXF, he observed that having two copies of the X chromosome was protective in bladder carcinogenesis via kdm6a gene modulation. When comparing XY versus XX, there was a 2.5-fold increase in cancer risk and when comparing testes versus ovaries, there was a 4.7-fold increase in cancer risk. Tumor infiltrating CD8+ T cells also demonstrated superior effector function in female mice. He concluded the talk by discussing decreased CD8+T cell exhaustion and suppressed tumor growth after castration in invivo studies.

In the last talk of the afternoon, Dr. Koti (Queen’s University) closed the session by addressing sex differences in responses to BCG induced B cell treatment of bladder cancer. She presented findings from her lab showing that female patients with high grade NMIBC have higher density of tumor infiltrating B cells and this was associated with shorter progression free survival and earlier recurrence. 4 Tertiary lymphoid structures (TLSs) are concentrations of immune cells that are found in the setting of chronic inflammation including cancer. In newer studies, she observed no difference in TLS from BCG responders and non-responders. However, she found that BCG induces TLS formation in the bladder microenvironment of female aging mice. Finally, she reported that decreased expansion of B-cells in male mice post BCG treatment.

 

Presented by:

  • Molly Ingersoll PhD, Research Director/Directeur de Recherche, Mucosal Inflammation and Immunity Group, Institut Pasteur & Institut Cochin
  • Hiroshi Miyamoto MD, PhD, Director of Genitourinary Pathology at the University of Rochester Medical Center.
  • Sean Li PhD, Associate Professor, Departments of Surgery and Urology, Boston Children’s Hospital and Harvard Medical School
  • Madhuri Koti DVM, MVSc, PhD Assistant Professor, Department of Biomedical and Molecular Sciences at Queen’s University

Written by: Valentina Grajales MD, MS, Urologic Oncology Fellow, Twitter: @ValGraj, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022



References: 

  1. Piasecka B, Duffy D, Urrutia A, Quach H, Patin E, Posseme C, Bergstedt J, Charbit B, Rouilly V, MacPherson CR, Hasan M, Albaud B, Gentien D, Fellay J, Albert ML, Quintana-Murci L; Milieu Intérieur Consortium. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E488-E497. doi: 10.1073/pnas.1714765115. Epub 2017 Dec 27. PMID: 29282317; PMCID: PMC5776984.
  2. Ide H, Inoue S, Mizushima T, Jiang G, Chuang KH, Oya M, Miyamoto H. Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer. Mol Cancer Ther. 2018 Jul;17(7):1566-1574. doi: 10.1158/1535-7163.MCT-17-1061. Epub 2018 May 2. PMID: 29720561.
  3. Miyamoto H, Yao JL, Chaux A, Zheng Y, Hsu I, Izumi K, Chang C, Messing EM, Netto GJ, Yeh S. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 2012 Jun;109(11):1716-26. doi: 10.1111/j.1464-410X.2011.10706.x. Epub 2012 Jan 5. PMID: 22221549.
  4. Chenard S, Jackson C, Vidotto T, Chen L, Hardy C, Jamaspishvilli T, Berman D, Siemens DR, Koti M. Sexual Dimorphism in Outcomes of Non-muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint. Eur Urol Open Sci. 2021 Jun 3;29:50-58. doi: 10.1016/j.euros.2021.05.002. PMID: 34337534; PMCID: PMC8317911.