Nature solves the mystery of acidic environments "assisting" tumor immunity.

Whether the body can produce highly effective antigen-specific T cells after contact with antigens depends on whether the immune system can clear the antigens in time.If antigens (such as malignant tumors) cannot be effectively removed, chronic antigen stimulation will lead to T cell function depletion, which is characterized by reduced effector function, decreased cytokine production and proliferation, and expression of inhibitory receptors (such as PD-1, CTLA-4) [1].at present, the research on these inhibitory receptors has become the focus of cancer immunotherapy.Vista (V-domain immunoglobin suppressor of T cell activation) is a ligand of B7 family, which is mainly expressed in bone marrow cells of circulating system and tumor. In addition, there is a small amount of expression in activated lymphocytes.in previous studies, it was found that vista can inhibit the activity of T cells and help tumor resist immunotherapy with PD-1 and ctla-1 antibodies [2,3].but the receptor protein of Vista has not been found. Therefore, we do not know how Vista can help tumor escape immunotherapy.recently, Professor Robert J. Johnston, from the Department of tumor immunology of Bristol Myers Squibb, published a report entitled "vista is an acidic pH selective life for" in nature They reported that PSGL-1 is a selective receptor of Vista under acidic pH conditions, thus explaining how Vista inhibits T cell activity and eventually leads to immune escape of tumor cells under acidic pH conditions of tumor microenvironment.the authors found that compared with other members of the immunoglobulin superfamily, the extracellular domain of Vista is rich in histidine residues.due to the imidazole ring on the side chain of histidine, it can bind H + under acidic conditions and protonation. Therefore, we speculate that vista may bind to its receptor and play a role in tumor microenvironment (pH can be as low as 5.85).sure enough, the experimental results showed that vista could directly bind to leukocytes at acidic pH (6.0), but not at normal physiological pH (7.4).in addition, we found that the monoclonal antibody of Vista, vista. 4 and the antibody with the same epitope can inhibit the binding of Vista to immune cells and enhance the function of T cells, while the monoclonal antibodies against other epitopes such as Vista. 5 have no effect.these results suggest that vista can selectively inhibit T cell function, but it is still unclear whether Vista binds to its receptors through histidine rich domains.further experiments showed that the antigenic epitopes of histidine residues enriched in Vista were recognized by the monoclonal antibody vista. This suggests that the protonation of histidine residues at acidic pH may be the key to the binding of Vista to receptors.therefore, the acid pH specific antibody vista.18 was obtained by point mutation screening of Vista. 4.it was found that vista.18 was bound to the histidine rich domain, while vista. 5 without blocking effect was bound to the opposite domain.in order to find the receptor of Vista, the authors incubated the modified Vista protein with CD4 + T cells at acidic pH, and finally enriched several potential target receptors, including PSGL-1 (P-selectin glycoprotein ligand-1).PSGL-1 has been identified as an inhibitory receptor of T cells and plays a role in chronic viral infection, tumor and autoimmune diseases [4]. in vitro experiments showed that PSGL-1 could specifically bind to Vista at acidic pH, and this binding could be inhibited by recombinant P-selectin and Vista antibody. in addition, the authors also found that, unlike P-selectin (the binding of PSGL-1 to P-selectin requires both sulfation and sialylation of its own tyrosine), the binding of Vista to PSGL-1 is only dependent on tyrosine sulfation. the structural data showed that the sulfated tyrosine residues y46 and Y48 of PSGL-1 could interact with histidine residues H153 and h154 of Vista, and the E56 and Y51 residues of PSGL-1 could interact with H98 and H100 of Vista. these results indicate that the binding of PSGL-1 to Vista is mediated by the sulfated tyrosine residues of PSGL-1 and the protonated histidine residues of Vista. finally, the anti-tumor immune function of Vista was explored. The authors found that treatment of tumor bearing mice with antibodies of Vista and PD-1 alone did not significantly inhibit the growth of tumor, but the combination of them had a significant effect. in addition, the combination therapy can significantly enhance the permeability of T cells to tumor cells and reduce the expression of T cell inhibitory receptors, including PD-1, LAG-3 and tam-3. in conclusion, this work not only found the selective receptor psgl1 of Vista under acidic pH conditions, but also made us better understand the specific molecular mechanism of Vista inhibiting T cell immune response at the molecular level. more interestingly, their work reveals that the function of T cells is also regulated by the acidic pH of tumor microenvironment, which may help us to explain some clinical phenomena observed so far. (1) Ribas, A. & amp; Wolchok, J. D. cancer immunotherapy using checkpoint blockade. Science 359, 1350 – 1355 (2018). 2. Gao, J. et al. Vista is an invasive immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. NAT. Med. 23, 551–555 (2017).3. Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl Acad. Sci. USA 116,1692–1697 (2019).4. Matsumoto, M., Miyasaka, M. & Hirata, T. P-selectin glycoprotein ligand-1 negatively regulates T-cell immune responses. J. Immunol. 183, 7204–7211 (2009).