(847) Diverse resident memory T-cell subsets differentiate in tumors to promote antitumor immunity and response to immune checkpoint blockade immunotherapy

Introduction/Rationale: The accumulation of CD103+CD8 resident memory T (TRM) cells in tumors is predictive of a response to PD-1 blockade. However, the nature of the TRM subsets regulating the response to other immune checkpoint inhibitors and their differentiation mechanisms in the tumor remain unclear.

Methods: Mouse tumor models, human cancer samples and cohorts, scRNAseq, immune cell imaging and functional assays.

Results: Our results show that while CD103+CD8 TRM promote the response to anti-PD-1 neutralizing antibodies, CD49a+CD4 TRM promote the response to anti-CTLA-4. Single-cell RNA sequencing on mouse tumor-infiltrating T lymphocytes (TIL) reveals a CD49a+CD4 TRM signature enriched in CTLA-4, ICOS, RUNX and residency-linked transcripts, amplified upon CTLA-4 blockade. Anti-CTLA-4 therapy leads to intratumoral expansion of CD49a+CD4 TRM and an increase in CD4 TIL-mediated cytotoxicity toward tumor cells. A CD49a+CD4 TRM signature enriched in CTLA-4 and cytotoxicity-linked transcripts is identified in TIL from human lung tumors and melanomas. Multiplex fluorescence immunohistochemistry on cohorts of anti-CTLA-4-plus-anti-PD-1-treated melanomas shows that an increase in the density of CD49a+CD4 TIL is associated with higher rates of progression-free survival. Our results also show that the formation of CD49a+CD4 and CD103+CD8 TRM in human lung tumors involves distinct transcription factors, and that the differentiation of functional CD4 and CD8 TRM within the tumor microenvironment requires different signaling pathways. Moreover, CD4 and CD8 TRM subsets display phenotypic and functional heterogeneity, and undertake distinct cellular interactions and molecular signals for potent cytotoxic activity and tumor progression control.

Conclusion: Our results support the conclusion that different CD4 and CD8 TRM subpopulations participate to antitumor immunity and response to immune checkpoint blockade, and that their differentiation in the tumor relies on specific cellular interactome and distinct signaling programs.