Abstract B040: Androgen signaling attenuates granzyme B production in CD8+ T cells in ICI-Colitis

Abstract Immune checkpoint inhibitor [ICI, e.g. anti-programmed death protein (anti-PD-1)] cancer therapies can cause autoimmune attack in healthy tissues [immune related adverse events (irAE)] in 60-70% of patients as a side effect. ICI-Colitis is a particularly severe irAE characterized by T cell destruction of the intestinal epithelium; it occurs in approximately 20% of patients and is a leading cause of hospitalizations and treatment-related death. Despite this clinical impact, patient specific risk factors for ICI-Colitis remain poorly understood. Spontaneous autoimmune diseases have a well established female predominance due to chromosomal and hormonal immune mechanisms, and emerging data suggest increased irAEs in women. Androgens, the predominant male sex hormone, can dampen immune responses to protect against autoimmunity. Androgens also influence anti-tumor immune responses during ICI therapy through modulation of exhaustion and cytotoxic effector function in CD8+ T cells. How sex hormones influence development of irAEs, including ICI-Colitis, is unknown. We used our established irAE mouse model in which ICI treatment of non-obese diabetic (NOD) mice causes autoimmune infiltration in multiple organs (including the colon) to test the impact of sex hormone loss by gonadectomy on irAEs. In intact male mice treated with ICI, there was an increase in IFNy, IL-17A, and TNF-alpha producing CD4+ and CD8+ T cells compared to isotype-control mice. Interestingly, loss of androgens (gonadectomy) increased the histologic severity of ICI-Colitis in male mice. Specifically, there were increased cytotoxic Granzyme B (GzmB)+ CD8+ T cells in the colon of gonadectomized male mice treated with ICI compared to their intact male counterparts. Gonadectomy in males was not associated with changes in IFNy, IL-17A, or TNF-alpha producing CD4+ or CD8+ T cells. Gonadectomy in female mice did not alter the frequency or severity of ICI-Colitis. These data suggest that androgens may be selectively inhibiting the GzmB production of CD8+ T cells to protect against ICI-Colitis. Indeed, we identified four putative androgen receptor binding sites (responsive elements) in the Gzmb promoter using the Find Individual Motif Occurrences (FIMO) and JASPAR databases that can be further interrogated. Taken together, these data suggest that androgens might play a protective role in ICI-Colitis and contribute to the emerging sex bias in irAEs through direct inhibition of GzmB production in CD8+ T cells in the colon. Citation Format: Esther M. Peluso, Amber Lu, Kyleigh Kimbrell, Jarod Olay, Maureen A. Su, Melissa G . Lechner. Androgen signaling attenuates granzyme B production in CD8+ T cells in ICI-Colitis [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B040.