Abstract 2582: Regulatory T cells restrain efficacy of immunotherapy in murine liver tumors

Abstract

Abstract Background: Checkpoint blockade immunotherapy (CBI) can induce a durable response for some patients with hepatic tumors, but many derive no or incomplete oncologic benefit for unclear reasons. Regulatory T cells (Tregs) in the liver play a central role in maintaining the tolerogenic local immune environment, both in homeostasis and disease. Here we sought to explore the impact of CBI on hepatic Tregs to determine if they play a role in CBI resistance of liver tumors in mice. Methods: High-dimensional flow cytometry was used to examine the ex vivo characteristics of lymphocytes from both tumor-free and orthotopic tumor-bearing livers of mice treated with CBI or other immunomodulatory agents. Results: All hepatic T cell subsets examined displayed higher proliferative and apoptotic indices compared with those of splenic T lymphocytes. We found that hepatic Tregs intensely proliferate and undergo apoptosis compared with splenic Tregs under homeostatic conditions. Hepatic Treg proliferation was enhanced after administration of CBI treatment. This effect was abrogated by co-treatment with sirolimus. CD8, macrophages, and the gut microbiome were found to be dispensable for the in vivo in response to αPD1. Co-treatment of mice with αPD1 and αCD25 sensitized MC38-bearing liver tumors. Conclusion: Murine liver Tregs naturally proliferate and undergo apoptosis due to the mTOR rheostat at homeostasis making them highly responsive to CBI. This behavior potentially explains liver-specific CBI-resistance in tumors. Citation Format: Benjamin L. Green, Chi Ma, Qianfei Zhang, Benjamin Ruf, Umberto Rosato, Jonathan Qi, Simon Wabitsch, Kylynda Bauer, Yuta Myojin, Justin McCallen, John C. McVey, Varun Subramanyam, Vanessa Catania, Amran Nur, Firouzeh Korangy, Changqing Xie, Tim F. Greten. Regulatory T cells restrain efficacy of immunotherapy in murine liver tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2582.