Abstract
Abstract Colorectal cancer (CRC) ranks among the most prevalent cancers worldwide, causing substantial mortality. The urgent need for effective treatments has driven research into immune checkpoint blockade (ICB) therapies, which have demonstrated significant clinical benefits across various cancer types. Despite the success of ICB therapies, a significant proportion of CRC patients exhibit resistance to treatment, prompting the identification of mechanisms that hinder therapy resistance or enhance treatment response. CRC cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro-tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. In this study, we found that colorectal tumors with high glutaminase (GLS) expression exhibit reduced T-cell infiltration and cytotoxicity, leading to poor clinical outcomes. To validate these findings, we applied the ovalbumin (OVA)/OT-I T cell-based cytotoxicity assay and the CRC patient-derived organoids (PDOs)/autologous T cell killing assay. Our results indicated that inhibition of GLS significantly enhanced T-cell cytotoxicity in vitro and ex vivo. Mechanistically, we elucidated that inhibition of GLS activated reactive oxygen species-related signaling pathways in tumor cells, thereby potentially increasing tumor immunogenicity by promoting antigen presentation. The combinational therapy of GLS inhibitor and ICB exhibited a superior tumor growth inhibitory effect in comparison with either of the monotherapies. These findings shed new light on clinical therapeutic strategies for CRC patients, offering a promising approach to enhance the efficacy of ICB therapy. Citation Format: Tao Yu, Kevin Van der Jeught, Haiqi Zhu, Zhuolong Zhou, Samantha Sharma, Sheng Liu, Ka Man So, Haniyeh Eyvani, Xiyu Wang, George E. Sandusky, Yunlong Liu, Mateusz Opyrchal, Sha Cao, Jun Wan, Chi Zhang, Xinna Zhang. Targeting glutamine metabolism potentiates antigen presentation in colorectal cancer [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 6741.