不同肿瘤驻留记忆 T 细胞亚群调控对抗 PD-1 和抗 CTLA-4 肿瘤免疫治疗的应答

The involvement of tumour-resident memory T (T RM ) cells in responses to immune checkpoint inhibitors remains unclear.

Here, we show that while CD103 + CD8 T RM cells are involved in response to PD-1 blockade, CD49a + CD4 T RM 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 T RM signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4.

CTLA-4 blockade expands CD49a + CD4 T RM cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49a + CD4 T RM 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 T RM cells may correspond to a predictive biomarker of response to combined immunotherapy.