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

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 2

UMCD6 antibody enhances cancer cell killing by PBMCs.

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UMCD6 antibody enhances cancer cell killing by PBMCs. Tumor cells were c...
Tumor cells were cocultured and imaged using an IncuCyte system that recorded tumor cell number (B, D, and F, red fluorescence with y axis log2) and cell death (A, C, and E, green fluorescence, caspase sensitive with y axis linear). (A and B) CD318-expressing MDA-MB-231 cancer cells were plated in a 96-well plate with a seeding density of 20,000 cells with 50,000 PBMCs. Enhanced killing of MDA-MB-231 HBCCs by PBMC was observed in the presence of anti-CD6 (UMCD6) or anti-CD318 (3a11) for caspase expression compared with control antibodies (UMCD6 vs. anti-vWF P = 0.000623; UMCD6 vs. 3a11 P = 0.00401; 3a11 vs. anti-vWF P = 0.0476) and tumor cell survival (UMCD6 vs. anti-vWF P = 0.00223; UMCD6 vs 3a11 P = 0.4507; 3a11 vs anti-vWF P = 0.0078). (C and D) MDA-MB-231 cells were plated at a seeding density of 20,000 cells per well. 50,000 PBMCs were added at 22 hours. Before addition to the cocultures, PBMCs were incubated for 1 hour at 37°C with UMCD6 or mouse IgG control antibodies. (E and F) LNCaP prostate cancer cells were plated at a seeding density of 20,000 cells per well. 50,000 PBMCs were added to the LNCaP cell cultures at 4 hours. Before addition to the cocultures, PBMCs were incubated with UMCD6 or IgG control antibodies. MDA HBCCs and LNCaP cells displayed profound enhancement of clumping and caspase expression in cocultures in which PBMCs were exposed to UMCD6 (A and C). MDA and LNCaP cells also displayed inhibited growth in the wells containing UMCD6-treated PBMCs (B and D). Statistical significance (*P < 0.05) was initially achieved for MDA-MB-231 between the UMCD6- and anti–LFA-1 IgG–treated cocultures at 39 hours (green, caspase cell death) and 51 hours (red, survival). Similarly, differences in LNCaP cell death became significant at 8.5 hours (E) and at 43.5 hours for survival (F) between UMCD6 and anti-vWF IgG cocultures. See Supplemental Videos 1–3 for MDA-231 breast cancer cell killing.