Combination therapy with IL15SA and ICB resulted in the greatest tumor killing and maintained an effector CD8 + T-cell population in the presence of imatinib. Combining an IL15 superagonist (IL15SA) with imatinib restored intratumoral effector CD8 + T-cell function and CD8 + T-cell intracellular PI3K signaling, resulting in greater tumor destruction. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8 + T cells but more naïve CD8 + T cells.
Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Imatinib reduced the frequency of effector CD8 + T cells and increased the frequency of naïve CD8 + T cells within mouse GIST, which coincided with altered tumor chemokine production, CD8 + T-cell recruitment, and reduced CD8 + T-cell intracellular PI3K signaling. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequencing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8 + T-cell subsets in a genetically engineered mouse model of GIST. Despite the presence of a robust immune CD8 + T-cell infiltrate, combining a TKI with immune-checkpoint blockade (ICB) in advanced GIST has achieved only modest effects. Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative.
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