Abstract 5641: Tumor cell intrinsic factors in colorectal cancer immune evasion

Abstract

Abstract The poor response of most colorectal cancer (CRC) patients to immunotherapy is a major unmet clinical need. Although early detection through screening has reduced CRC incidence, the prognosis for metastatic CRC is poor. In the past decade, immune checkpoint inhibitors (ICIs) have been a major clinical breakthrough with promising clinical benefits in many cancer types, but its efficacy is limited in most (~85%) CRC patients. ICIs preferentially have robust responses from tumors with pre-existing T cell infiltration. However, most CRC lacks robust T-cell infiltration due to immune evasion mechanisms. Therefore, it is crucial to characterize factors shaping immune evasion to improve the response to ICIs. We hypothesize that targeting tumor-cell intrinsic factors can overcome T cell exclusion and will sensitize the tumor to ICIs. To elucidate the factors underlying ICI resistance, it is critical that preclinical models faithfully recapitulate the tumor physiology and genetics of the human disease. Therefore, we developed a tumor organoid (tumoroids) model system adapted from Jacks lab that harbors shApc, KrasG12D, p53-/- and Smad4-/- (shAKPS) mutations, which are co-mutated with high frequency and associated with poor prognosis. We demonstrated that tumoroids with only shApc and KrasG12D mutations can form a solid tumor in two weeks. Addition of p53-/- and Smad4-/- mutations drives invasiveness and metastasis. The shAKPS tumoroids present key features of advanced CRC that are unresponsive to ICIs including invasive tumor, metastasis, and T cell exclusion. Using CRISPR/Cas9 screening and integrative immune score analysis, we identified potential immune evasive genes. To define their expression profile in the tumor, we performed TCGA data analysis in fourteen different cancer types. Furthermore, we performed correlation tests to determine their role in immune cell infiltration and T cell dysfunction. Our results show that these immune suppressive genes are overexpressed in tumor tissues, and negatively correlate with CD8+ T cell infiltration. Our findings suggest that overexpression of immune suppressive genes in cancer cells may cause T cell dysfunction and exclusion in tumors. Furthermore, the functional role of these immune suppressive genes will be characterized using shAKPS mutant organoids and in vivo orthotopic CRC tumor models. Citation Format: Dechen Wangmo, Xianda Zhao, Angelo Yuan, Travis Gates, Subree Subramanian. Tumor cell intrinsic factors in colorectal cancer immune evasion [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 5641.