Damei Isabelle, Caidi Aziza, Auclin Edouard, Adam Julien, Mella Sébastien, Hasan Milena, Tartour Eric, Robert Caroline, Corgnac Stéphanie, Mami-Chouaib Fathia
INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Faculte de Médecine-Universite Paris-Sud, Université Paris-Saclay, Villejuif, France.
Department of Medicine, Institut Bergonié, Bordeaux, France.
Nat Commun. 2025 Jul 1;16(1):5588. doi: 10.1038/s41467-025-60657-w.
The involvement of tumour-resident memory T (T) cells in responses to immune checkpoint inhibitors remains unclear. Here, we show that while CD103CD8 T cells are involved in response to PD-1 blockade, CD49aCD4 T 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 CD49aCD4 T signature, enriched in Ctla-4 transcripts, exacerbated upon anti-CTLA-4. CTLA-4 blockade expands CD49aCD4 T cells and increases tumour-specific CD4-TIL-mediated cytotoxicity. A CD49aCD4 T 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 CD49aCD4 T-cell density in pre-treatment tumours, which correlates with higher rates of patient progression-free survival. Thus, CD49aCD4 T cells may correspond to a predictive biomarker of response to combined immunotherapy.
肿瘤驻留记忆T（T）细胞在免疫检查点抑制剂反应中的作用仍不清楚。在这里，我们表明，虽然CD103⁺CD8⁺ T细胞参与对PD-1阻断的反应，但CD49a⁺CD4⁺ T细胞是对抗CTLA-4反应所必需的。使用临床前小鼠模型，我们证明在接受抗CD8和抗CD103阻断抗体攻击的动物中，抗PD-1治疗的益处受到损害。相比之下，抗CD4和抗CD49a中和抗体降低了抗CTLA-4的益处。对肿瘤浸润性T淋巴细胞（TIL）进行单细胞RNA测序揭示了一个CD49a⁺CD4⁺ T细胞特征，该特征富含Ctla-4转录本，在抗CTLA-4治疗后加剧。CTLA-4阻断可扩增CD49a⁺CD4⁺ T细胞并增加肿瘤特异性CD4⁺-TIL介导的细胞毒性。在人类TIL中也鉴定出富含CTLA-4和细胞毒性相关转录本的CD49a⁺CD4⁺ T细胞特征。在一组接受抗CTLA-4加抗PD-1治疗的黑色素瘤患者中进行的多重免疫组织化学分析显示，治疗前肿瘤中CD49a⁺CD4⁺ T细胞密度增加，这与患者更高的无进展生存率相关。因此，CD49a⁺CD4⁺ T细胞可能对应于联合免疫治疗反应的预测生物标志物。
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