Abstract 542: Development of novel syngeneic tumor models with intrinsic or extrinsic resistance mechanisms to PD-1 blockade

Abstract Programmed cell death-1 (PD-1) blockade has demonstrated remarkable clinical efficacy across various tumor types. However, the current PD-1 blockade monotherapy benefits only a small proportion of patients, and primary or acquired resistance can ultimately lead to cancer progression in clinical settings. Understanding the underlying mechanisms of resistance is both necessary and urgent to enhance clinical outcomes. Increasing evidence suggests that resistance to PD-1 therapy can arise from both tumor-cell-intrinsic and tumor-cell-extrinsic factors. Loss-of-function mutations in the antigen presentation pathway and downstream elements represent intrinsic mechanisms, while tumor-infiltrating immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) contribute to immune tolerance as extrinsic factors. Currently, the rational design of combination therapies based on these resistance mechanisms remains to be achieved. In this study, we developed two types of anti-PD-1 antibody-resistant models based on the intrinsic anti-PD-1 treatment-sensitive MC38 models. These models include genetically engineered resistant models with B2M or STK11 knockout (KO) and induced resistant models through in vivo progressive drug selection. STK11 KO mutations resulted in reduced expression of PD-L1 on tumor cells and a lower infiltration of CD8+ cytotoxic T lymphocytes in the tumor microenvironment, while B2M KO led to a lack of antigen presentation on the tumor cell surface, blocking the binding of the anti-PD-1 antibody. In terms of the induced anti-PD-1 resistant models, a higher proportion of immunosuppressive cells, including Tregs, MDSCs, and TAMs, were observed in the tumor microenvironment compared to the parental counterparts, contributing to immune escape from PD-1 blockade. These models simulate extrinsic and intrinsic mechanism-based anti-PD-1 resistance, allowing for the identification of combination therapies to overcome resistance to anti-PD-1. Our study enhances our understanding of the biological basis of anti-PD-1 resistance and supports the discovery of mechanistically-designed combination therapies to overcome resistance to anti-PD-1 therapy, potentially broadening its clinical applicability. Citation Format: Xiaomin Wang, Ziwei Zhang, Longzhou Liu, Xue Zhang, Dong Wang, Nengwei Xu, Xiangnan Qiang, Qingyang Gu, Jian Xiang, Zhixiang Zhang. Development of novel syngeneic tumor models with intrinsic or extrinsic resistance mechanisms to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 542.