Abstract
Abstract Background: Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumor-intrinsic and acquired immunotherapy resistance. Methods: A novel immunophenotype-based subtyping algorithm was established to analyze tumor patient-derived bulk transcriptomic data. Gene set enrichment assays (GSEA), in vitro cell models, multiple syngeneic murine tumor models, and immune-checkpoint blockade (ICB) therapy were utilized. Results: Our algorithm stratified human GC and showed that immune desert- and excluded-type tumors are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signaling is highly enriched in immune desert-type GC, and syngeneic murine tumors exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identifies a panel of receptor tyrosine kinases (RTKs) as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activates the tumor-intrinsic SNAI1/2-IFN-γ signaling axis and impedes the EMT program converting immune desert-type tumors to immune inflamed-type tumors, sensitizing these mesenchymal-like ‘cold’ tumors to CTLA4 blockade. Conclusion: We develop a novel immunophenotype-based algorithm to reclassify GC into immune inflamed, excluded, and desert subtypes. Our analysis identified major signaling pathways and potential druggable targets relevant to patient groups, especially for refractory immune desert-type/‘cold’ tumors. Dovitinib, an RTK inhibitor, sensitizes desert-type immune-cold GCs to CTLA4 blockade and possibly in a broad spectrum of other solid tumors. Citation Format: Heng Lu, Longlong Cao, Mohammed Soutto, Nadeem Bhat, Zheng Chen, Dunfa Peng, Ahmed Gomaa, Sachiyo Nomura, Jashodeep Datta, Alexander Zaika, Wael El-Rifai. Dovitinib restricts EMT and promotes T cell recruitment to immune-desert gastric cancers via tumor-intrinsic IFN-γ signaling [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 3237.