VISTA is an acidic pH-selective ligand for PSGL-1

Robert J. Johnston (), Linhui Julie Su, Jason Pinckney, David Critton, Eric Boyer, Arathi Krishnakumar, Martin Corbett, Andrew L. Rankin, Rose Dibella, Lynne Campbell, Gaelle H. Martin, Hadia Lemar, Thomas Cayton, Richard Y.-C. Huang, Xiaodi Deng, Akbar Nayeem, Haibin Chen, Burce Ergel, Joseph M. Rizzo, Aaron P. Yamniuk, Sanjib Dutta, Justine Ngo, Andrea Olga Shorts, Radha Ramakrishnan, Alexander Kozhich, Jim Holloway, Hua Fang, Ying-Kai Wang, Zheng Yang, Kader Thiam, Ginger Rakestraw, Arvind Rajpal, Paul Sheppard, Michael Quigley, Keith S. Bahjat and Alan J. Korman
Additional contact information
Robert J. Johnston: Bristol-Myers Squibb
Linhui Julie Su: Bristol-Myers Squibb
Jason Pinckney: Bristol-Myers Squibb
David Critton: Bristol-Myers Squibb
Eric Boyer: Bristol-Myers Squibb
Arathi Krishnakumar: Bristol-Myers Squibb
Martin Corbett: Bristol-Myers Squibb
Andrew L. Rankin: Five Prime Therapeutics
Rose Dibella: Bristol-Myers Squibb
Lynne Campbell: Bristol-Myers Squibb
Gaelle H. Martin: genOway
Hadia Lemar: Bristol-Myers Squibb
Thomas Cayton: Bristol-Myers Squibb
Richard Y.-C. Huang: Bristol-Myers Squibb
Xiaodi Deng: Bristol-Myers Squibb
Akbar Nayeem: Bristol-Myers Squibb
Haibin Chen: Bristol-Myers Squibb
Burce Ergel: Bristol-Myers Squibb
Joseph M. Rizzo: Bristol-Myers Squibb
Aaron P. Yamniuk: Bristol-Myers Squibb
Sanjib Dutta: Bristol-Myers Squibb
Justine Ngo: Bristol-Myers Squibb
Andrea Olga Shorts: Bristol-Myers Squibb
Radha Ramakrishnan: Bristol-Myers Squibb
Alexander Kozhich: Bristol-Myers Squibb
Jim Holloway: Bristol-Myers Squibb
Hua Fang: Bristol-Myers Squibb
Ying-Kai Wang: Bristol-Myers Squibb
Zheng Yang: Bristol-Myers Squibb
Kader Thiam: genOway
Ginger Rakestraw: Bristol-Myers Squibb
Arvind Rajpal: Bristol-Myers Squibb
Paul Sheppard: Bristol-Myers Squibb
Michael Quigley: Bristol-Myers Squibb
Keith S. Bahjat: Bristol-Myers Squibb
Alan J. Korman: Bristol-Myers Squibb

Nature, 2019, vol. 574, issue 7779, 565-570

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1674-5

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