A new Nature report by Bristol-Myers Squibb provides new insights into VISTA biology and design of combination therapies

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Johnston, R.J. et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019 Oct.

Immune checkpoint inhibitors play a critical role in cancer suppression.^1,2 For this reason, antibodies targeting immune checkpoint inhibitors such as CTLA-4 and PD-1 have become standard of care in an increasing number of solid tumors, including metastatic melanomas, non-small-cell lung carcinomas and liver cancer.³ These immunotherapies offer patients a durable remission from diseases whose outcomes were previously invariably terminal; over time, however, some tumors become resistant to such molecules due to innate and acquired resistance. These limitations have pushed scientists to understand the biological mechanisms responsible for the development of such resistances, and establish new therapeutic strategies.⁴

VISTA is an immune checkpoint inhibitor that has been identified as a potential mediator of resistance to anti-CTLA-4 and anti-PD-1 immunotherapies.^5,6 However, to date, it has not been frequently used for therapeutic intervention due to a lack of understanding of its mechanism of action in immune responses.

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Along these lines, a study conducted by a group of researchers at Bristol-Myers Squibb, freshly published in Nature, shed some light on VISTA and its interaction with PSGL-1.⁷ In particular, Johnston and colleagues found that VISTA binds and suppresses T cells at acidic pH such as that typically measured in tumor microenvironments. Pharmacokinetic experiments conducted on our humanized VISTA mice treated with VISTA-blocking antibodies showed indeed that acidic pH-selective antibodies accumulate preferentially within tumors and exhibit longer serum mean resistance time than non-pH-selective antibodies. Moreover, the authors demonstrated that tumor growth in human VISTA Knockin mice bearing mouse colorectal carcinoma MC38 cells is significantly reduced in animals treated with combination therapy (anti-VISTA and anti-PD-1) compared to those that received monotherapy (anti-PD-1).

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References:

1. Paluch, Christopher, et al. "Immune checkpoints as therapeutic targets in autoimmunity." Front Immunol. 2018 Oct 8
2. Armezzani, A. "Immune checkpoint inhibitors: A strategy to tackle cancer?" genOway, 2019 Jul
3. Darvin, Pramod, et al. "Immune checkpoint inhibitors: recent progress and potential biomarkers." Exp Mol Med. 2018 Dec 13
4. Wang, Jinghua, et al. "VSIG‐3 as a ligand of VISTA inhibits human T‐cell function." Immunology. 2019 Jan
5. Kakavand, Hojabr, et al. "Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients." Mod Pathol. 2017 Dec
6. Nowak, Elizabeth C., et al. "Immunoregulatory functions of VISTA." Immunol Rev. 2017 Mar
7. Johnston, Robert J., et al. "VISTA is an acidic pH-selective ligand for PSGL-1." Nature. 2019 Oct