Alteber Zoya, Kotturi Maya F, Whelan Sarah, Ganguly Sudipto, Weyl Emmanuel, Pardoll Drew M, Hunter John, Ophir Eran
Compugen Ltd, Holon, Israel.
Compugen USA, Inc., South San Francisco, California.
Cancer Discov. 2021 May;11(5):1040-1051. doi: 10.1158/2159-8290.CD-20-1248. Epub 2021 Mar 9.
Therapeutic antibodies targeting the CTLA4/PD-1 pathways have revolutionized cancer immunotherapy by eliciting durable remission in patients with cancer. However, relapse following early response, attributable to primary and adaptive resistance, is frequently observed. Additional immunomodulatory pathways are being studied in patients with primary or acquired resistance to CTLA4 or PD-1 blockade. The DNAM1 axis is a potent coregulator of innate and adaptive immunity whose other components include the immunoglobulin receptors TIGIT, PVRIG, and CD96, and their nectin and nectin-like ligands. We review the basic biology and therapeutic relevance of this family, which has begun to show promise in cancer clinical trials. SIGNIFICANCE: Recent studies have outlined the immuno-oncologic ascendancy of coinhibitory receptors in the DNAM1 axis such as TIGIT and PVRIG and, to a lesser extent, CD96. Biological elucidation backed by ongoing clinical trials of single-agent therapy directed against TIGIT or PVRIG is beginning to provide the rationale for testing combination regimens of DNAM1 axis blockers in conjunction with anti-PD-1/PD-L1 agents.
靶向CTLA4/PD-1通路的治疗性抗体通过使癌症患者获得持久缓解，彻底改变了癌症免疫治疗。然而，早期缓解后因原发性和适应性耐药导致的复发很常见。针对CTLA4或PD-1阻断产生原发性或获得性耐药的患者，正在研究其他免疫调节通路。DNAM1轴是先天性和适应性免疫的有效共调节因子，其其他组成部分包括免疫球蛋白受体TIGIT、PVRIG和CD96，以及它们的nectin和nectin样配体。我们综述了这个家族的基础生物学和治疗相关性，该家族已在癌症临床试验中初显成效。意义：最近的研究概述了DNAM1轴中如TIGIT和PVRIG等共抑制受体在免疫肿瘤学中的优势，以及在较小程度上CD96的优势。针对TIGIT或PVRIG的单药治疗正在进行的临床试验所支持的生物学阐释，开始为测试DNAM1轴阻滞剂与抗PD-1/PD-L1药物联合使用的联合方案提供理论依据。
