Abstract C173: Negative selection of ligand-receptor interactions mediating lymphocyte infiltration confers melanoma resistance to Immune Checkpoint Blockade therapy by turning hot tumors to cold

Abstract Immune checkpoint blockade (ICB) is a promising cancer therapy; however, response rates remain less than desired (less than ~40%) and resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (Immunotherapy Resistance cell-cell Interaction Scanner), a machine learning method aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to underlie ICB resistance in the tumor microenvironment (TME). Our approach considers two key components that such interactions should fulfill: they should be (1) differentially activated between the pre-treatment and post-treatment non-responderpatients, and (2) they should be predictive of ICB response in pre-treatment patients. We trained the model on the five largest publicly available melanoma bulk transcriptomics ICB cohorts and demonstrated its superior performance versus two states-of-the-art transcriptomics-based prediction methods (IMPRES and TIDE) in predicting ICB therapy response both in terms of RECIST criteria and patient survival. We further validated our identified resistance relevant LRIs in a melanoma single cell ICB cohort. Strikingly, LRIs highly activated in the pre-treatment group showed stronger predictive power for ICB response compared to the post-treatment non-responder group, which implies a potential negative selection of LRIs by tumors. Notably, many of these LRIs are mediating lymphocyte infiltration within the TME. Reassuringly, we further find a strong correlation between the activity of these LRIs and CD8+ T cells infiltration levels in the TME and are highly enriched in hot tumors in an independent cohort. Overall, these findings suggest that the tumor may develop resistance to ICB via inhibiting lymphocytes infiltration relevant ligand-receptor interactions, turning hot tumors to cold. Citation Format: Sahil Sahni, Kun Wang, Binbin Wang, Saugato Rahman Dhruba, Di Wu, Matthew Nagy, Eytan Ruppin. Negative selection of ligand-receptor interactions mediating lymphocyte infiltration confers melanoma resistance to Immune Checkpoint Blockade therapy by turning hot tumors to cold [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C173.