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Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation. See related Spotlight on p. 489

Introduction: Targeted therapy with tyrosine kinase inhibitors (TKI) including imatinib is effective in treating gastrointestinal stromal tumor (GIST), but resistance often develops within 18 months. Despite a robust immune T cell infiltrate, combining TKIs with immune checkpoint inhibitors has largely been unsuccessful in treating advanced GIST. The superagonist IL15/1L15Rα has shown promise in a number of cancer types. The objective of this study was to determine the effects of TKI therapy on intratumoral T cells in GIST and evaluate IL15/1L15Rα as an adjunctive therapy. Methods: KitV558Δ/+ mice were treated with imatinib (600mg/L in water) and/or IL15/IL15Rα (2ug/12ug/dose, 3x/week), for 1-4 weeks and evaluated by TCRB sequencing (Immunoseq), RNA-seq, and flow cytometry (n=4-5/group). Intratumoral immune cells from KitV558Δ/+ mice were evaluated by single cell RNA sequencing (scRNAseq) (n=3). Results: RNA-seq of sorted CD8 T cells following 1 week of imatinib treatment suggested intratumoral CD8 T cells gain antigen experience but lose their effector profile, as cd44, sell, and tcf7 increased while gzmb and tnfrsf9 decreased (p Citation Format: Andrew Tieniber, Andrew Hanna, Benjamin Medina, Kevin Do, Lillian Levin, Ferdiando Rossi, Ronald DeMatteo. Oncogenic kinase therapy restricts CD8 T cell differentiation and clonal expansion [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P050.