作者
Robert J. Johnston,Linhui Julie Su,Jason Pinckney,David Critton,E. W. Boyer,Arathi Krishnakumar,Martin J. Corbett,Andrew L. Rankin,Rose A. DiBella,Lynne Campbell,Gaëlle Martin,Hadia Lemar,Thomas Cayton,Richard Y.‐C. Huang,Xiaolong Deng,Akbar Nayeem,Haibin Chen,Burçe Ergel,Joseph M. Rizzo,Aaron P. Yamniuk,Sanjib Dutta,Justine Ngo,Andrea Olga Shorts,Radha Ramakrishnan,Alexander Kozhich,James L. Holloway,Huihui Fang,Ying-Kai Wang,Zheng Yang,Kader Thiam,Ginger Rakestraw,Arvind Rajpal,Paul W. Sheppard,Michael Quigley,Keith S. Bahjat,Alan J. Korman
摘要
Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement.