细胞毒性T细胞
免疫系统
癌症研究
生物
肿瘤微环境
CD8型
癌症免疫疗法
免疫学
免疫疗法
NKG2D公司
癌细胞
癌症
生物化学
遗传学
体外
作者
Mikel Gurrea-Rubio,Qi Wu,M. Asif Amin,Pei‐Suen Tsou,Phillip L. Campbell,Camila E. Amarista,Yuzo Ikari,William D. Brodie,Megan N. Mattichak,Sei Muraoka,Peggy M. Randon,Matthew E. Lind,Jeffrey H. Ruth,Yang Mao-Draayer,Shengli Ding,Xiling Shen,Laura A. Cooney,Feng Lin,David A. Fox
出处
期刊:Research Square - Research Square
日期:2023-10-09
标识
DOI:10.21203/rs.3.rs-3405677/v1
摘要
Abstract Immune checkpoint inhibitors (ICIs) have demonstrated efficacy and improved survival in a growing number of cancers. Despite their success, ICIs are associated with immune-related adverse events that can interfere with their use. Therefore, safer approaches are needed. CD6, expressed by T-lymphocytes and human NK cells, engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6 is a target protein for regulating immune responses and is required for the development of several mouse models of autoimmunity. Interestingly, CD6 is exclusively expressed on immune cells while CD318 is strongly expressed on most cancers. Here we demonstrate that disrupting the CD6-CD318 axis with UMCD6, an anti-CD6 monoclonal antibody, prolongs survival of mice in xenograft models of human breast and prostate cancer, treated with infusions of human lymphocytes. Analysis of tumor-infiltrating immune cells showed that augmentation of lymphocyte cytotoxicity by UMCD6 is due to effects of this antibody on NK, NKT and CD8+ T cells. Tumor-infiltrating cytotoxic lymphocytes were found in higher proportions and were activated in UMCD6-treated mice compared to controls. Similar changes in gene expression were observed by RNA-seq analysis of NK cells treated with UMCD6. Particularly, UMCD6 up-regulated the NKG2D-DAP10 complex and activated PI3K. Thus, the CD6-CD318 axis can regulate the activation state of cytotoxic lymphocytes and their positioning within the tumor microenvironment.
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