Different tumour-resident memory T-cell subsets regulate responses to anti-PD-1 and anti-CTLA-4 cancer immunotherapies
Isabelle Damei, Aziza Caidi, Édouard Auclin, Julien Adam, Sébastien Mella, Milena Hasan, Éric Tartour, Caroline Robert, Stéphanie Corgnac, Fathia Mami‐Chouaib
Abstract
The involvement of tumour-resident memory T (TRM) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103+CD8 TRM cells are involved in response to PD-1 blockade, CD49a+CD4 TRM cells are required for the response to anti-CTLA-4. Using preclinical mouse models, we demonstrate that the benefits of anti-PD-1 treatment are compromised in animals challenged with anti-CD8 and anti-CD103 blocking antibodies. By contrast, the benefits of anti-CTLA-4 are decreased by anti-CD4 and anti-CD49a neutralizing antibodies. Single-cell RNA sequencing on tumour-infiltrating T-lymphocytes (TIL) reveals a CD49a+CD4 TRM signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49a+CD4 TRM cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a+CD4 TRM signature enriched in CTLA-4 and cytotoxicity-linked transcripts is also identified in human TILs. Multiplex immunohistochemistry in a cohort of anti-CTLA-4-plus-anti-PD-1-treated melanomas reveals an increase in CD49a+CD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49a+CD4 TRM cells may correspond to a predictive biomarker of response to combined immunotherapy. While the involvement of CD8 tissue-resident memory T (TRM) cells in the response to ICB therapy has been reported, less is known about the relevance of CD4 TRM cells. Here, using mouse cancer models and human melanoma samples and NSCLC dataset, the authors show that CD49a+ CD4 TRM cells often accumulate in pre-treatment tumours, and their presence correlates with a favourable response to anti-CTLA-4 therapy.