A small molecule inhibitor of VSIG-8 prevents its binding to VISTA
A small molecule inhibitor of VSIG-8 prevents its binding to VISTA
复制标题
DOI：
10.1007/s10637-022-01244-4
复制
发表时间：
2022-04-11
影响因子：
3.4
通讯作者：
Liu, Jun
中科院分区：
文献类型：
--
作者：
Chen, Wenting;Qie, Chenxin;Liu, Jun
含有V区免疫球蛋白的T细胞活化抑制因子（VISTA）是B7家族的一个独特成员，是癌症、自身免疫性疾病和炎性疾病的一个有吸引力的免疫靶点。2016年，一项专利证明了V-Set和含有免疫球蛋白结构域的8（VSIG-8）是推定的VISTA受体。拮抗剂或激动剂可以令人信服地调节VISTA及其相互作用配偶体，这将极大地有益于许多疾病的治疗。通过酶联免疫吸附测定（ELISA）、微量热泳（MST）和免疫共沉淀（Co-IP）实验测量VISTA和VSIG-8的相互作用。在体外和体内评价VSIG-8抑制剂L557-0155的生物活性。通过MST，人VISTA与人VSIG-8结合的Kd值为1.58 +/-0.44 μ M。当VISTA的相关氨基酸结合位点突变为丙氨酸时，VISTA与VSIG-8之间的相互作用消失。VSIG-8蛋白在VISTA过表达细胞中诱导IL-2水平降低，但在VISTA（-/-）细胞中诱导IL-2水平升高。此外，VSIG-8抑制剂L557-0155促进PBMC中的细胞因子产生和细胞增殖，并抑制黑色素瘤生长。VSIG-8/VISTA共抑制通路可能为人类癌症的治疗提供新的策略，并且VSIG-8阻断可能增加抗肿瘤免疫。本研究首次报道了VSIG-8与VISTA相互作用，抑制T细胞功能。
The V-region immunoglobulin-containing suppressor of T cell activation (VISTA), a unique B7 family member, is an attractive immunotherapeutic target for cancer, autoimmune and inflammatory diseases. In 2016, a patent demonstrated V-Set and Immunoglobulin domain containing 8 (VSIG-8) was the putative VISTA receptor. Antagonistic or agonistic agents can conceivably modulate VISTA and its interacting partners, which will greatly benefit the treatment of many diseases. The interaction of VISTA and VSIG-8 were measured by Enzyme-linked Immuno Sorbent Assay (ELISA), Microscale Thermophoresis (MST) and coimmunoprecipitation (Co-IP) experiments. The bioactivity of VSIG-8 inhibitor L557-0155 was evaluated in vitro and in vivo. K-d value of human VISTA binding to human VSIG-8 was 1.58 +/- 0.44 mu M by MST. When the related amino acid binding site of VISTA was mutated to alanine, the interaction between VISTA and VSIG-8 disappeared. VSIG-8 protein induced an decrease in the level of IL-2 in VISTA-overexpressing cells but a increase in VISTA(-/-) cells. Furthermore, VSIG-8 inhibitor L557-0155 promoted cytokine production and cell proliferation in PBMCs and suppressed melanoma growth. VSIG-8/VISTA coinhibitory pathway may provide a novel strategy for the treatment of human cancers, and VSIG-8 blockade may increase antitumor immunity. This study was the first time to report that VSIG-8 interacts with VISTA, and inhibited T cell function.