Distinct tumor-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies

The nature of the tumor-resident memory T (TRM) cells regulating responses to immune checkpoint inhibitors remains unclear. We show here, that CD8+CD103+ TRM cells are involved in controlling tumor progression under conditions of PD-1 blockade, whereas the response to anti-CTLA-4 antibodies requires CD4+CD49a+ TRM. The benefits of anti-PD-1 antibodies, but not of anti-CTLA-4 antibodies, are compromised in mice challenged with anti-CD8 and anti-CD103 blocking antibodies, and in CD8- and CD103-knockout mice in the absence of wild-type CD8+ T-cell transfer. By contrast, the benefits of CTLA-4 blockade are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumor-infiltrating T lymphocytes (TIL) revealed a CD4+CD49a+ TRM signature enriched in CTLA-4, ICOS, RUNX and residency-linked transcripts, exacerbated upon CTLA-4 blockade. CTLA-4 blockade leads to the intratumoral expansion of CD4+CD49a+ TRM cells and an increase in CD4+ TIL-mediated cytotoxicity to target cells. A CD4+CD49a+ TRM signature enriched in CTLA-4 and cytotoxicity-linked transcripts was also identified in TIL from human lung carcinoma and melanoma. Multiplex fluorescence immunohistochemistry on a cohort of anti-CTLA-4-plus-anti-PD-1 antibody-treated melanomas showed that an increase in the density of CD4+CD49a+ T cells in pre-treatment tumors was associated with much higher rates of progression-free survival. Thus, tumor CD4+CD49a+ TRM cells play a key role in CTLA-4 blockade and could be considered a predictive biomarker of the response to combined immunotherapy.

• Type: Transcriptome Analysis
• Archiver: European Genome-Phenome Archive (EGA)