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

Isabelle Damei, Aziza Caidi, Edouard Auclin, Julien Adam, Sébastien Mella, Milena Hasan, Eric Tartour, Caroline Robert, Stéphanie Corgnac and Fathia Mami-Chouaib ()
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Isabelle Damei: Université Paris-Saclay
Aziza Caidi: Université Paris-Saclay
Edouard Auclin: Institut Bergonié
Julien Adam: Université Paris-Saclay
Sébastien Mella: Université Paris Cité
Milena Hasan: Université Paris Cité
Eric Tartour: Service d’Immunologie Biologique
Caroline Robert: Institut Gustave Roussy
Stéphanie Corgnac: Université Paris-Saclay
Fathia Mami-Chouaib: Université Paris-Saclay

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60657-w

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