This study investigates the impact of imatinib, a tyrosine kinase inhibitor (TKI), on CD8+ T cells in gastrointestinal stromal tumors (GIST). The authors found that imatinib reduced effector CD8+ T cells and increased naive CD8+ T cells, limiting the antitumor response. Adding an IL15 superagonist (IL15SA) to imatinib restored effector T-cell function and improved tumor destruction. The combination of IL15SA and immune-checkpoint blockades (ICB) with imatinib was most effective in killing tumors.
Summary:
Gastrointestinal stromal tumors (GISTs) are the most common human sarcomas, primarily caused by mutations in the KIT or PDGFRA genes. Imatinib has significantly improved the survival of patients with advanced GIST but is rarely curative due to secondary mutations. Despite the robust immune infiltrate, combining imatinib with ICB has shown limited efficacy in advanced GIST. Therefore, the goal of this study was to identify the limitations imposed by imatinib on the antitumor immune response by analyzing CD8+ T-cell subsets in a genetically engineered mouse model of GIST.
First, to characterize the baseline phenotype of tumor-infiltrating CD8+ T-cell, bulk RNA-sequencing of CD8+ T-cells from tumors, lymph nodes, and spleens in Kit mutant mice was utilized, which showed higher inflammatory markers in tumor-infiltrating cells compared to more naive T-cells in lymph nodes and spleens. Flow cytometry confirmed these findings, showing a predominance of effector memory subtypes in tumors.
Second, to determine the effects of imatinib therapy on tumor-infiltrating CD8+ T-cells, repeat bulk RNA-seq on CD8+ T-cells from imatinib-treated and untreated Kit mutant mice was used, which revealed increased naive-type transcripts in tumor-infiltrating cells of treated mice, not seen in lymph nodes or spleens. Single-cell RNA-seq and flow cytometry showed this shift became more pronounced with prolonged treatment.
Third, to elucidate the mechanisms driving the shift from effector memory-type to naïve-type phenotypes in the setting of imatinib therapy, the authors performed several hypothesis-driven experiments which demonstrated that changes in tumoral chemokine production, impaired PI3K signaling, and decreased clonal expansion may all be implicated in the phenotypic shift following imatinib therapy. This suggests alterations in recruitment, antigen presentation, and/or co-stimulation mechanisms may be at play.
Fourth, to assess presence of phenotypic shifts in human GISTs, flow cytometry on human GIST specimens from patients treated with imatinib was performed, which showed a decrease in effector memory-type and increase in naive-type CD8+ T-cells in imatinib-sensitive tumors, consistent with the murine model.
Fifth, to investigate strategies that may improve antitumoral CD8+ T-cell response, several KitV558/+ mice were treated with imatinib, an IL15 super-agonist (IL15SA), or imatinib plus an IL15SA for one week. IL15 stimulation, combined with imatinib, showed a synergistic effect, reducing tumor weight by 30%. Additional experiments indicated improved PI3K pathway activity and a greater presence of effector memory-type CD8+ T-cells with triple therapy (imatinib, IL15 super-agonist, and anti-PD-1).
As this study demonstrates the complex interplay of immune cells, it also shows that pinpointing specific therapeutic targets is challenging. Additionally, the human GIST samples showed variability in immune cell populations and responses to imatinib, which may affect the reproducibility and applicability of findings across different patient populations. While the combination of TKIs and immunotherapies shows promise, further research is needed to determine the optimal therapeutic timing and sequencing.
Bottom Line: Imatinib therapy alters intra-tumoral CD8+ T-cell phenotype composition and antitumor activity in gastrointestinal stromal tumors. Combining T-cell agonistic therapy with imatinib improves CD8+ T-cell antitumor function. These results provide a rationale for including T-cell agonistic therapies in the treatment of GIST with TKI.