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

Abstract

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 sequencing (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 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. 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 naïve 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.

• Authors: Andrew D Tieniber, Andrew N Hanna, Benjamin D Medina, Gerardo A Vitiello, Mark S Etherington, Mengyuan Liu, Kevin J Do, Ferdinando Rossi, Ronald P DeMatteo
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 10 Issue 10 Pg. 1210-1223 (10 04 2022) ISSN: 2326-6074 [Electronic] United States
• PMID: 35917579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Chemokines
• Immune Checkpoint Inhibitors
• Interleukin-15
• Protein Kinase Inhibitors
• Imatinib Mesylate
• Protein-Tyrosine Kinases

Topics

• Animals
• CD8-Positive T-Lymphocytes
• Cell Line, Tumor
• Chemokines
• Gastrointestinal Stromal Tumors (drug therapy)
• Humans
• Imatinib Mesylate (pharmacology, therapeutic use)
• Immune Checkpoint Inhibitors
• Interleukin-15 (pharmacology)
• Mice
• Phosphatidylinositol 3-Kinases
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (pharmacology)