CD6 is a target for cancer immunotherapy.

Jeffrey H Ruth,Phillip L Campbell,Venkateshwar G Keshamouni,Pei-Suen Tsou,Mikel Gurrea-Rubio,Qi Wu,Nora G Singer,M Asif Amin,Rosemary J Gedert,Feng Lin,Kalana S Athukorala,Daniel P Weber,Stephanie M Rasmussen,Peggy M Randon,David A Fox,Matthew E Lind,Yang Mao-Draayer,Thomas M Lanigan

doi:10.1172/jci.insight.145662

Abstract

Limitations of checkpoint inhibitor cancer immunotherapy include induction of autoimmune syndromes and resistance of many cancers. Since CD318, a novel CD6 ligand, is associated with the aggressiveness and metastatic potential of human cancers, we tested the effect of an anti-CD6 monoclonal antibody, UMCD6, on killing of cancer cells by human lymphocytes. UMCD6 augmented killing of breast, lung, and prostate cancer cells through direct effects on both CD8+ T cells and NK cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xenotransplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and downregulated expression of the inhibitory receptor NKG2A on both NK cells and CD8+ T cells, with concurrent increases in perforin and granzyme B production. The combined capability of an anti-CD6 monoclonal antibody to control autoimmunity through effects on CD4+ lymphocyte differentiation while enhancing killing of cancer cells through distinct effects on CD8+ and NK cells opens a potential new approach to cancer immunotherapy that would suppress rather than instigate autoimmunity.

Highlights

Checkpoint inhibitor therapy, directed at programmed cell death 1 (PD-1), PD-1 ligand 1 (PD-L1), or cytotoxic T lymphocyte–associated protein 4 (CTLA-4), has revolutionized cancer immunotherapy
All lines tested expressed moderate to high levels of CD166/activated leukocyte cell adhesion molecule (ALCAM), a ligand of CD6 that is found on activated leukocytes, cancer cells, and many normal tissue cell populations [16] (Figure 1A)
The data in this report establish that the anti-CD6 mAb UMCD6 powerfully stimulates the ability of human lymphocytes to kill cancer cells of multiple types

Summary

Introduction

Checkpoint inhibitor therapy, directed at programmed cell death 1 (PD-1), PD-1 ligand 1 (PD-L1), or cytotoxic T lymphocyte–associated protein 4 (CTLA-4), has revolutionized cancer immunotherapy. Cancers respond with varying efficacy to checkpoint inhibition, and many patients experience severe autoimmune-related adverse events with these therapies [1]. Additional targets are needed on cancer cells and lymphocytes that enhance immune cell elimination of tumors without engendering autoimmune toxicities through induction of lymphocyte self-reactivity. CD318 (CDCP1, TRASK, SIMA135, or gp140) is a cell surface glycoprotein that is widely expressed by cancer cells, and its degree of expression correlates with cancer aggressiveness and metastatic potential [2,3,4]. We recently discovered that CD318 is a second ligand for the CD6 T cell surface glycoprotein [5]

Methods

Results

Conclusion