Gurrea‐Rubio et al. showed prolonged survival of SCID mice bearing s.c. human breast or prostate tumors that were infused intratumorally with human lymphocytes and treated with the IgG1 mAb UMCD6, specific for human CD6 – an immune cell-expressed scavenger receptor, which has as ligands CD318, which is expressed on most cancers, and adhesion molecule CD166. UMCD6 boosted perforin expression and cytolysis by tumor-infiltrating, CD6-expressing NK, NKT, and T cells, and induced resident immune cell killing of patient-derived lung cancer cells in micro-organospheres comparably to nivolumab. UMCD6 upregulated the NKG2D–DAP10 activation receptor complex and its target, PI3K, in human NK-92 cells.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Internal Medicine, Division of Rheumatology, University of Michigan and Autoimmunity Center of Excellence, Ann Arbor, MI, USA.(2) Department of Neurology, Univers
Author Info: (1) Department of Internal Medicine, Division of Rheumatology, University of Michigan and Autoimmunity Center of Excellence, Ann Arbor, MI, USA.(2) Department of Neurology, University of Michigan, Ann Arbor, MI, USA. (3) Oklahoma Medical Research Foundation, 825 NE 13th St, Oklahoma City, OK, 73104, USA. (4) Xilis, Inc., Durham, NC, USA. (5) Department of Immunity and Inflammation, Lerner Research Institute, Cleveland, OH, USA. (6) Department of Internal Medicine, Division of Rheumatology, University of Michigan and Autoimmunity Center of Excellence, Ann Arbor, MI, USA. dfox@med.umich.edu.
