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 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 or prostate cancer cells through direct effects on both CD8+ T cells and natural killer (NK) cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the PD-1/PD-L1 axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xeno-transplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and down-regulated 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 capabilities 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.
Jeffrey H. Ruth, Mikel Gurrea-Rubio, Kalana S. Athukorala, Stephanie M. Rasmussen, Daniel Weber, Peggy M. Randon, Rosemary J. Gedert, Matthew E. Lind, Mohammad Asif Amin, Phillip L. Campbell, Pei-Suen Tsou, Yang Mao-Draayer, Qi Wu, Thomas M. Lanigan, Venkateshwar G. Keshamouni, Nora G. Singer, Feng Lin, David A Fox