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 1

Expression of CD318 on multiple cancer cell lines.

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Expression of CD318 on multiple cancer cell lines. (A) Flow cytometry re...
(A) Flow cytometry revealed robust expression of CD318 on the breast cancer lines BT-549, T-47D, MDA-MB-361, BT-20, MDA-MB-436, MDA-MB-231, and SK-BR-3; the prostate cancer lines PC3 and LNCaP; the melanoma cell lines A375 and A375-MA2; and the non–small cell lung cancer line NCI-H460. Tumor lines with low expression of CD318 included MCF7 (breast), UM-MEL-1 (melanoma), and HS587 (lung) — not pictured here. (B) FACS analysis was confirmed by immunoblotting of tumor cell lysates from MDA-MB-231 and MCF7 human breast cancer cells (HBCCs). IFN-γ had a negligible effect on CD318 expression on HBCCs, distinct from the previously observed induction of CD318 by IFN-γ on cultured synovial fibroblasts. (C and D) MDA-MB-231 and MCF7 HBCCs were plated in a 96-well plate at 20,000 cells per well, followed by addition of 50,000 CFSE-labeled T cells (n = 64). Adhesion was measured after 1 hour at 37°C as CFSE green fluorescence using a BioTek Synergy Plate Reader at 40× magnification. More lymphocytes bound to the CD318+ MDA-MB-231 cells than to the CD318– MCF7 cells. (E) Soluble CD318 is shed from CD318+ cancer cells. ELISA for sCD318 in culture supernatants of CD318– MCF7 cells and CD318+ MDA cells shows that HBCCs that express CD318 can also shed sCD318 into cell culture supernatants at concentrations previously shown to induce lymphocyte chemotaxis.