Abstract 5830: Presence of androgens improves efficacy of PD1 blockade
Authors: Vargas-Delgado María Elena , Meier Lara , Waizenegger Jonas , Oberbauer Julia , Berenbrok Nikolaus , Engelmann Janik , Gensch Victoria , Heilmann Franziska , Reinert Jochim , Riecken Kristoffer , Fehse Boris , Lotter Hannelore , Schwinge Dorothee , Schramm Christoph , Mittruecker Hans-Willi , Ben-Batalla Isabel , Loges Sonja 
Published: June 2023

Abstract
Immune therapies have revolutionized the treatment of cancer, however, until now only a minority of patients derive long-term benefit. Notably, despite widely reported significant differences between the immune system of males and females, there continues to exist a knowledge gap regarding sex disparities in anti-cancer immune responses. Recent meta-analyses indicate that immune checkpoint blockade (ICB) treatment has higher efficacy in male patients compared to females, regardless of the cancer type. To investigate the mechanisms underlying these sex-specific differences we utilized the syngeneic colorectal cancer model MC38 because it mirrors the clinical situation yielding responding and non-responding mice. Therefore, we inoculated tumor cells subcutaneously (s.c.) into male and female mice, and treated them with either IgG2a control Ab or anti-PD1 Ab. When analyzing the tumor response to anti-PD1 treatment we observed significant sex-biased growth kinetics upon ICB favoring males. To asses a potential role of androgens in impacting observed sex differences to ICB response in vivo, we performed surgical androgen deprivation therapy (orchiectomy) in male mice, as well as sham-surgery in male and female mice as control. After a recovery period, we proceeded with s.c. cell injection and ICB treatment as previously described. Sham male mice showed a very high response rate to anti-PD1 (92%) compared to sham females (58%), but more importantly, testosterone suppression by surgical androgen deprivation therapy led to a lower response rate of castrated mice (71%). To further confirm whether the presence of testosterone was beneficial for ICB response, we implanted s.c. sham or testosterone pumps into male and female mice and proceeded as before. Males with sham pumps showed a very high response rate to anti-PD1 (90%) compared to females with sham pumps (50%), while testosterone supplementation in females led to enhanced response rate (85%). Overall, this demonstrated that regardless of biological sex, presence of testosterone is sufficient to positively impact ICB therapy outcome. Furthermore, immunophenotyping analysis by flow cytometry showed that females supplemented with testosterone and treated with anti-PD1 had significantly increased intratumoral stem-like CD8+TCF1+PD1+ T cells compared to sham females. Additionally, these findings also correlated with enhanced intratumoral terminal differentiated effector CD8+TCF1-PD1+ T cells in both sham males and females supplemented with testosterone, compared to sham females. In summary, androgens can modulate anti-cancer immune responses by contributing to a more sustained anti-tumor CD8+ T cell response and consequently better responses upon treatment with anti-PD1. These findings are in concordance with male cancer patients responding better to ICB and warrant therapy escalation in female patients.
Citation Format: María Elena Vargas-Delgado, Lara Meier, Jonas Waizenegger, Julia Oberbauer, Nikolaus Berenbrok, Janik Engelmann, Victoria Gensch, Franziska Heilmann, Jochim Reinert, Kristoffer Riecken, Boris Fehse, Hannelore Lotter, Dorothee Schwinge, Christoph Schramm, Hans-Willi Mittruecker, Isabel Ben-Batalla, Sonja Loges. Presence of androgens improves efficacy of PD1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5830.