提吉特
CD28
癌症研究
封锁
细胞毒性T细胞
CD8型
T细胞
阿替唑单抗
生物
受体
细胞生物学
免疫系统
免疫疗法
免疫学
无容量
生物化学
体外
作者
Karl L. Banta,Xiaozheng Xu,Avantika S. Chitre,Amelia Au-Yeung,Chikara Takahashi,William O’Gorman,Thomas D. Wu,Stephanie Mittman,Rafael Cubas,Laëtitia Comps-Agrar,Amit Fulzele,Eric J. Bennett,Jane L. Grogan,Enfu Hui,Eugene Y. Chiang,Ira Mellman
出处
期刊:Immunity
[Elsevier]
日期:2022-03-01
卷期号:55 (3): 512-526.e9
被引量:79
标识
DOI:10.1016/j.immuni.2022.02.005
摘要
Dual blockade of the PD-1 and TIGIT coinhibitory receptors on T cells shows promising early results in cancer patients. Here, we studied the mechanisms whereby PD-1 and/or TIGIT blockade modulate anti-tumor CD8+ T cells. Although PD-1 and TIGIT are thought to regulate different costimulatory receptors (CD28 and CD226), effectiveness of PD-1 or TIGIT inhibition in preclinical tumor models was reduced in the absence of CD226. CD226 expression associated with clinical benefit in patients with non-small cell lung carcinoma (NSCLC) treated with anti-PD-L1 antibody atezolizumab. CD226 and CD28 were co-expressed on NSCLC infiltrating CD8+ T cells poised for expansion. Mechanistically, PD-1 inhibited phosphorylation of both CD226 and CD28 via its ITIM-containing intracellular domain (ICD); TIGIT’s ICD was dispensable, with TIGIT restricting CD226 co-stimulation by blocking interaction with their common ligand PVR (CD155). Thus, full restoration of CD226 signaling, and optimal anti-tumor CD8+ T cell responses, requires blockade of TIGIT and PD-1, providing a mechanistic rationale for combinatorial targeting in the clinic.
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