Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma
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Background
Immune checkpoint inhibitors (ICI) are efficacious in many solid tumors, but response in glioma is restricted to a small subgroup. The determinants of response and resistance to ICI remain poorly understood.
Methods
Here we exploit a syngeneic hypermutated high-grade glioma model with dichotomous response to combined PD-1 and CTLA-4 inhibition to unravel determinants of tumor-infiltrating T-cells driving response. Tumor-infiltrating T-cells from ICI-responsive and non-responsive tumors were analyzed by single-cell RNA and T-cell receptor sequencing and tumor-reactive T-cell receptor clonotypes were functionally validated to characterize their transcriptional phenotypes. We verify our findings in IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab.
Results
ICI response was associated with intratumoral clonal expansion of tumor-reactive cytotoxic T-cells and increased infiltration of CXCR6+ CD4+ tissue resident memory T-cells (Trm). CD4⁺ stem-like memory T-cells in responding tumors demonstrated elevated interferon responses, following trajectories toward clonally expanded Trm, versus trajectories toward exhaustion in non-responsive tumors. In responsive tumors, CD4+ Trm interacted with infiltrating CXCR3+ tumor-reactive and clonally expanded, yet transcriptionally versatile cytotoxic T-cells. Probing the post neoadjuvant ICI high-grade glioma patient tissue dataset, we confirmed increased CXCR6 expression in CD4+ T cells and the association of CD4+ Trm with prolonged overall survival.
Conclusion
These findings identify CD4⁺ tissue-resident memory T-cells as determinants of ICI response in IDH1 wildtype high-grade glioma and warrant their further investigation to improve immunotherapy outcomes.
Key points
- Stem-like T cell-derived CD4+ CXCR6+ Trm and tumor-reactive CXCR3+ CD8+ T-cells characterize ICI response in IDH1 wildtype high-grade glioma.
- In IDH1 wildtype glioblastoma patients, CXCR6+ CD4+ Trm associate with prolonged survival after neoadjuvant ICI
Importance of the study
We show that CD4+ tissue resident memory cells (Trm) interact with clonal cytotoxic T-cells and are associated with IDH1 wildtype high grade glioma response to ICI and prolonged survival in a syngeneic tumor model and patients treated with neoadjuvant pembrolizumab. Our findings highlight the predictive potential of this specific T cell population, and warrant investigation of CD4+ Trm-targeted combined immunotherapy.
