Abstract 3169: Decoupling the correlation between cytotoxic and exhausted T lymphocyte transcriptomic signatures in melanoma enhances immunotherapy response prediction

Background: Cytotoxic T lymphocytes (CTL) play a crucial role in anti-cancer immunity. Progression of CTL to exhausted T lymphocytes (ETL) that overexpress inhibitory receptors can substantially decrease effector cytokines production and diminish cytolytic activity in tumor microenvironment (TME). However, while the activity levels of CTL and ETL are considered important determinants of immune checkpoint inhibitors (ICIs) response, it has been repeatedly observed that their predictive power is quite limited. Studying this conundrum on a large scale across the TCGA cohort, we find that ETL and CTL activity (estimated based on conventional gene signatures in the bulk tumor expression) is strongly positively correlated in most cancer types. We thus hypothesized that their limited predictive power may arise due to this high expression concordance, such that their opposing associations with response effectively cancel each other. Methods and Results: Aiming to find conditions where the association between these CD8+ T cell states and ICIs response is enhanced, we analyzed TCGA melanoma bulk gene expression via an interaction linear regression model to identify a set of genes whose expression diminishes the CTL and ETL correlation as much as possible. We further tested this decoupling signature (DS) in several independent melanoma bulk expression ICIs cohorts, showing that in high-DS patients, the correlation between ETL and CTL activities is indeed markedly lower than in the low-DS patient groups. Second, this successful decoupling now increases the power of CTL activity in predicting ICIs response in high DS patients, making it superior to other state-of-art ICIs prediction transcriptomic signatures. Significance: These results demonstrate the utility of a new decoupling score for boosting the power of CTL activity in predicting ICIs response in melanoma. Citation Format: Binbin Wang, Kun Wang, Peng Jiang, Eytan Ruppin. Decoupling the correlation between cytotoxic and exhausted T lymphocyte transcriptomic signatures in melanoma enhances immunotherapy response prediction [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 3169.