CD6 is a target for cancer immunotherapy
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
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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Research Article Immunology

CD6 is a target for cancer immunotherapy

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 4

Effect of UMCD6 on breast cancer cell killing by PBMCs compared with effects of checkpoint inhibitor immune therapeutics directed at the PD-1/PD-L1 axis.

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Effect of UMCD6 on breast cancer cell killing by PBMCs compared with eff...
(A and B) MDA-MB-231 tumor cells were plated in a 96-well plate at 20,000 cells/well. 50,000 PBMCs were added to the MDA-MB-231 cell cultures at 8 hours. Before addition to the cocultures, PBMCs were incubated for 1 hour at 37°C with UMCD6, vWF-IgG, or the same concentration of pembrolizumab or nivolumab, all at 10 μg/mL. Cancer cell killing was measured by the number of breast cancer cells present in each well (red fluorescence, tumor cell survival, with y axis log2) and cell death (green fluorescence, caspase sensitive, with y axis linear). Peak killing of cancer cells occurred around 61 hours, at which time MDA-MB-231 cells displayed profound caspase expression compared with the anti-vWF–treated wells (A; P = 1.712 × 10–14 at 61 hours). Statistical significance for caspase expression was initially achieved for MDA-MB-231 cell death at 31 hours for UMCD6 versus pembrolizumab and nivolumab — and at 30 hours for UMCD6 versus control IgG. MDA-MD-231 cells also showed inhibited growth and survival when exposed to the UMCD6-treated PBMC compared with the IgG control group from the beginning of the experiment that persisted and increased through 143 hours (B; UMCD6 vs. anti-vWF P = 5.757 × 10–9, UMCD6 vs. pembrolizumab P = 7.260 × 10–8, UMCD6 vs. nivolumab P = 7.186 × 10–10 at the final time point). (C) Single images of tumor cells in coculture with PBMCs and various antibody treatments. Hour 30 shows a coculture of PBMCs (small, round black cells) with dying tumor cells expressing caspase in the plate wells treated with UMCD6 (arrow). By 61 hours, wells treated with UMCD6 showed significantly more tumor cells with pronounced caspase expression that contained fewer tumor cells compared with cocultures treated with pembrolizumab, nivolumab, anti-vWF, or caspase reagent control culture. All images were taken at 20× magnification.