Tyrosine Kinase Inhibition Alters Intratumoral CD8+ T-cell Subtype Composition and Activity

Targeted therapy with a tyrosine kinase inhibitor (TKI) such as imatinib is effective in treating gastrointestinal stromal tumor (GIST), but it is rarely curative. 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. To identify limitations imposed by imatinib on the antitumor immune response, we performed bulk RNA sequenc-ing (RNA-seq), single-cell RNA-seq, and flow cytometry to phenotype CD8(+) T-cell subsets in a genetically engineered mouse model of GIST. Imatinib reduced the frequency of effector CD8(+) T cells and increased the frequency of naeurove CD8(+) T cells within mouse GIST, which coincided with altered tumor che-mokine production, CD8(+) T-cell recruitment, and reduced CD8(+) T-cell intracellular PI3K signaling. Imatinib also failed to induce intratumoral T-cell receptor (TCR) clonal expansion. Consistent with these findings, human GISTs sensitive to imatinib harbored fewer effector CD8(+) T cells but more naeurove CD8(+) T cells. 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. 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. Our findings highlight the impact of oncogene inhibition on intratumoral CD8(+) T cells and support the use of agonistic T-cell therapy during TKI and/or ICB administration.

Automated summary

Imatinib treatment reduces effector CD8(+) T cells and increases naïve CD8(+) T cells in GIST, impacting tumor chemokine production, T-cell recruitment, and signaling pathways. Combining IL15 superagonist with imatinib restores effector CD8(+) T cell function, leading to greater tumor destruction and improved outcomes, suggesting potential for T-cell therapy during TKI and/or ICB administration.