Friday, April 25, 2025
4/25/2025
Immunotherapy of prostate cancer using an anti-CD6 monoclonal antibody - PROJECT SUMMARY/ABSTRACT Limitations of checkpoint inhibitor cancer treatment include precipitation of autoimmunity and resistance to immunotherapy. For some cancers, notably prostate, lymphocytes are unable to infiltrate the cancer microenvironment. Therefore, new approaches and targets are required. Here we present CD6, a cell surface glycoprotein expressed by most T-lymphocytes and human natural killer (NK) cells, that engages in cell-cell interactions by binding to its ligands CD166 (ALCAM) and CD318 (CDCP1). CD6-/- and CD318-/- mice are healthy and are resistant to induction of T cell dependent autoimmune models of multiple sclerosis, uveitis and rheumatoid arthritis. Moreover, in CD6-humanized mice a monoclonal anti-human CD6 antibody that we developed, termed UMCD6, is a strikingly effective treatment for these autoimmune conditions. Both CD166 and CD318, the two ligands of CD6, are highly expressed by many cancers, and expression of CD318 correlates with aggressiveness and metastasis for many types of human cancers including prostate cancer. CD318 can also be shed by cancer cells, and its soluble form (sCD318) is chemotactic for NK cells and T cells. We have recently found that prostate cancer cell lines hyper-express and hyper-shed sCD318, creating a gradient that will halt lymphocyte migration prior to entry into the tumor microenvironment. Additionally, we tested the effect of blocking the CD6-CD318 axis with UMCD6 on the ability of human lymphocytes to kill human prostate cancer cells. We found that UMCD6 enhanced lymphocyte-mediated prostate cancer cell death and reduced cancer cell survival. We hypothesize that UMCD6 acts directly on CD8+ T cells and NK cells and can produce a complete response in vivo of human prostate cancer in immune deficient mice. We also propose that UMCD6 orchestrates prostate cancer cell death by extensive alteration of gene expression in NK cells and CD8+ T cells, thereby “licensing” these cells to kill cancer cells more aggressively. We will evaluate the efficacy of UMCD6 using repeated administration of UMCD6 and human lymphocytes to treat human prostate cancers xenografted into scid-beige mice. We will also demonstrate that high concentrations of sCD318 shed from prostate cancer can exclude lymphocytes from entering prostate cancers in vivo, unless CD6 is internalized. To verify that the in vivo mechanisms of the anticancer effects of UMCD6 reflect the pattern of altered gene expression in lymphocytes in vitro, we will perform single cell RNA-seq and multicolor flow cytometry on tumor-infiltrating lymphocytes (TILs). We will also assess the significance of upregulated stimulatory receptors by using blocking antibodies against these receptors in cancer cell killing assays. These experiments are structured to provide a compelling rationale for advancing CD6-targeted immunotherapy into clinical trials in human prostate cancer.
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