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CD6 is a target for cancer immunotherapy
Jeffrey H. Ruth, … , Feng Lin, David A. Fox
Jeffrey H. Ruth, … , Feng Lin, David A. Fox
Published January 26, 2021
Citation Information: JCI Insight. 2021;6(5):e145662. https://doi.org/10.1172/jci.insight.145662.
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Research Article Immunology

CD6 is a target for cancer immunotherapy

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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.

Authors

Jeffrey H. Ruth, Mikel Gurrea-Rubio, Kalana S. Athukorala, Stephanie M. Rasmussen, Daniel P. Weber, Peggy M. Randon, Rosemary J. Gedert, Matthew E. Lind, M. 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

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Figure 5

CD6+ NK cells treated with UMCD6 are highly effective at killing MDA-MB-231 tumor cells.

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CD6+ NK cells treated with UMCD6 are highly effective at killing MDA-MB-...
(A and B) Tumor cell killing assays were set up using 50,000 immune cells and 20,000 MDA-MB-231 HBCCs and antibodies at 10 μg/mL. PBMCs preincubated with UMCD6 killed tumor cells much more effectively than PBMCs preincubated with IgG control antibody, pembrolizumab, or nivolumab (A; red fluorescence, tumor cell survival, with y axis log2) and cell death (B; green fluorescence, caspase sensitive, with y axis linear). (C and D) Isolated CD8+ cells showed enhanced killing and lower tumor cell survival in cocultures with UMCD6 compared with the other antibodies. (E and F) Only UMCD6-induced tumor cell killing by purified NK cells.

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