Johnston et al. investigated the function of VISTA, a B7 family ligand expressed on myeloid cells and at low levels on activated T cells. The ligand for VISTA was identified as PSGL-1, which it bound under acidic conditions, mediated by histidine residues on the VISTA extracellular domain. VISTA acted as a co-inhibitor of T cells at an acidic pH, reminiscent of the TME, suppressing proliferation, IFNγ production, and NF-κB phosphorylation. VISTA-blocking antibodies, which were also pH sensitive, restored T cell responsiveness and, when combined with anti-PD-1, increased T cell infiltration and enhanced antitumor efficacy in MC38-bearing mice.
Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer(1,2). 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 malignancies(3). 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.
Author Info: (1) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. robert.johnston@bms.com. (2) Selection Technologies and Protein Engineering, Bristol-Myers Squibb, Cambr
Author Info: (1) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. robert.johnston@bms.com. (2) Selection Technologies and Protein Engineering, Bristol-Myers Squibb, Cambridge, MA, USA. (3) Biomolecular Characterization, Bristol-Myers Squibb, Cambridge, MA, USA. (4) Molecular Structure and Design, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (5) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (6) Proteomics Discovery, Bristol-Myers Squibb, Hopewell, NJ, USA. (7) Protein Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (8) Immuno-Oncology Discovery, Five Prime Therapeutics, South San Francisco, CA, USA. (9) Selection Technologies and Protein Engineering, Bristol-Myers Squibb, Cambridge, MA, USA. (10) Selection Technologies and Protein Engineering, Bristol-Myers Squibb, Cambridge, MA, USA. (11) genOway, Lyon, France. (12) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (13) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (14) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (15) Protein Therapeutics and Biologics Lead Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (16) Molecular Structure and Design, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (17) Protein Therapeutics and Biologics Lead Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (18) Protein Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (19) Protein Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (20) Protein Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (21) Biomolecular Characterization, Bristol-Myers Squibb, Cambridge, MA, USA. (22) Translational Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (23) Translational Sciences, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (24) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (25) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (26) Translational Bioinformatics, Bristol-Myers Squibb, Redwood City, CA, USA. (27) Lead Discovery and Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (28) Lead Discovery and Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (29) Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Lawrenceville, NJ, USA. (30) genOway, Lyon, France. (31) Selection Technologies and Protein Engineering, Bristol-Myers Squibb, Cambridge, MA, USA. (32) Protein Therapeutics and Biologics Lead Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (33) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (34) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (35) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. (36) Immuno-Oncology Discovery, Bristol-Myers Squibb, Redwood City, CA, USA. Vir Biotechnology, San Francisco, California, USA.
