The interaction of CD4(+) helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response
The interaction of CD4(+) helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response
复制标题
CD4(+)辅助性T细胞与树突状细胞的相互作用塑造了肿瘤微环境和免疫检查点阻断反应
DOI：
10.1038/s43018-022-00338-5
复制
发表时间：
2022-03-03
期刊：
影响因子：
22.7
通讯作者：
Amit, Ido
中科院分区：
文献类型：
--
作者：
Cohen, Merav;Giladi, Amir;Amit, Ido
尽管T细胞具有重要的调节作用和治疗效力，但肿瘤微环境中T细胞和抗原提呈髓系细胞之间相互作用的分子特征仍然很少。在这里，我们使用物理相互作用细胞的RNA测序(PIC-seq)系统地描述了这些相互作用，发现在人类非小细胞肺癌的肿瘤微环境中，CD4(+)PD-1(+)CXCL13(+)T细胞是与抗原提呈细胞的主要相互作用枢纽。我们将这种克隆性扩增的、肿瘤特异性的和保守的T细胞亚群称为辅助性T细胞(THT)。THT细胞在体外和卵白蛋白特异性的α-βTCR CD4(+)T细胞模型中的重建表明，THT程序是由呈递肿瘤抗原的树突状细胞在肿瘤引流淋巴结中启动的，并且它们的功能对于利用抗PD-1治疗的抗肿瘤反应是重要的。我们的分子和功能发现支持调节树突状细胞相互作用检查点作为免疫治疗的主要干预策略。Amit和他的同事报告说，在非小细胞肺癌中，CD4(+)PD-1(+)CXCL13(+)T细胞亚群与抗原提呈细胞的特异性相互作用重新编程了肿瘤微环境和对免疫检查点抑制剂的反应。
Despite their key regulatory role and therapeutic potency, the molecular signatures of interactions between T cells and antigen-presenting myeloid cells within the tumor microenvironment remain poorly characterized. Here, we systematically characterize these interactions using RNA sequencing of physically interacting cells (PIC-seq) and find that CD4(+)PD-1(+)CXCL13(+) T cells are a major interacting hub with antigen-presenting cells in the tumor microenvironment of human non-small cell lung carcinoma. We define this clonally expanded, tumor-specific and conserved T-cell subset as T-helper tumor (Tht) cells. Reconstitution of Tht cells in vitro and in an ovalbumin-specific alpha beta TCR CD4(+) T-cell mouse model, shows that the Tht program is primed in tumor-draining lymph nodes by dendritic cells presenting tumor antigens, and that their function is important for harnessing the antitumor response of anti-PD-1 treatment. Our molecular and functional findings support the modulation of Tht-dendritic cell interaction checkpoints as a major interventional strategy in immunotherapy.Amit and colleagues report that the specific interaction of a CD4(+)PD-1(+)CXCL13(+) T-cell subset with antigen-presenting cells reprograms the tumor microenvironment and response to immune checkpoint inhibitors in non-small cell lung cancer.