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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tyrosine kinase inhibitors (TKIs) like imatinib are effective against gastrointestinal stromal tumors (GIST) but rarely curative.
• Combining TKIs with immune-checkpoint blockade (ICB) shows limited efficacy in advanced GIST, despite CD8+ T-cell presence.

Purpose of the Study:

• To investigate how imatinib affects the anti-tumor immune response, specifically CD8+ T-cell subsets in GIST.
• To identify strategies to overcome imatinib-induced immune suppression in GIST.

Main Methods:

• Utilized a genetically engineered mouse model of GIST.
• Employed bulk and single-cell RNA sequencing (RNA-seq) and flow cytometry to analyze CD8+ T-cell populations.
• Assessed the impact of imatinib, IL-15 superagonist (IL15SA), and ICB, alone and in combination.

Main Results:

• Imatinib decreased effector CD8+ T cells and increased naive CD8+ T cells in GIST, impairing T-cell signaling and recruitment.
• Imatinib failed to promote intratumoral T-cell receptor (TCR) clonal expansion, a pattern mirrored in human GIST.
• Combination therapy with IL15SA and imatinib restored CD8+ T-cell function and enhanced tumor destruction; adding ICB yielded maximal tumor killing.

Conclusions:

• Oncogene inhibition by imatinib negatively impacts intratumoral CD8+ T cells in GIST.
• IL-15 superagonists can restore CD8+ T-cell function in the presence of TKIs.
• Combination therapy involving TKIs, IL15SA, and ICB shows promise for enhancing anti-GIST immunity and treatment outcomes.