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VISTA Is An Acidic PH-selective Ligand For PSGL-1

Robert J. Johnston, L. J. Su, J. Pinckney, D. Critton, E. Boyer, Arathi M Krishnakumar, M. Corbett, A. L. Rankin, Rose A. Dibella, L. Campbell, G. Martin, Hadia Lemar, T. Cayton, Richard Y.-C. Huang, X. Deng, A. Nayeem, Haibin Chen, B. Ergel, Joseph M. Rizzo, A. Yamniuk, S. Dutta, J. Ngo, A. Shorts, R. Ramakrishnan, Alexander Kozhich, J. Holloway, H. Fang, Ying-Kai Wang, Z. Yang, K. Thiam, G. Rakestraw, Arvind Rajpal, P. Sheppard, M. Quigley, K. Bahjat, A. Korman
Published 2019 · Chemistry, Medicine

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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. V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.
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