Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (T_FR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating T_FR cells. Both T_FR cell deficiency and the depletion of T_FR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy.

免疫检查点阻断 (ICB) 在提高抗肿瘤免疫力方面已显示出显着的临床成功。然而，其细胞靶点的广度和具体的作用方式仍然难以捉摸。我们发现肿瘤浸润性滤泡调节性 T (T _FR ) 细胞在几种癌症类型的肿瘤组织中普遍存在。它们主要位于三级淋巴结构内，与具有克隆和发育关系的调节性 T 细胞相比，表现出优越的抑制能力和体内持久性。在同基因肿瘤模型中，抗 PD-1 治疗增加了肿瘤浸润性 T _FR细胞的数量。T _FR细胞缺乏和 T _FR耗竭在抗 PD-1 治疗之前具有抗 CTLA-4 的细胞可改善小鼠的肿瘤控制。值得注意的是，在 271 名黑色素瘤患者的队列中，与抗 PD-1 或​​抗 CTLA-4、抗-PD-1，然后是抗 CTLA-4 进展或联合治疗。