Editorial: Prostate Cancer Research: Tools, Cancer Cell Types, Molecular Targets

Alvin Y. Liu ^1* Hung-Ming Lam ²

• ¹ Department of Urology and Institute for Stem Cells and Regenerative Medicine, University of Washington, Seattle, United States
• ² University of Washington, Seattle, Washington, United States

Tumor microenvironment (TME) plays a key role in how tumors respond to therapies, and potential mechanisms of treatment resistance. San Jose et al. reviewed the PCa immunome (cells of the immune system), which is characterized as an immunologically "cold" tumor due to low T-cell response to the cancer. Tumor immune evasion is enhanced by decreases in effector T cells and increases in regulatory T cells. How tumor cells affect cells of the immune system is largely unknown. The CD profiles of prostate (as described in Tools) showed a sizable population of infiltrating CD45+ white blood cells. Over 70 of the CD specificities tested could be detected by immunohistochemistry, including CD3 (T cell activating cells), CD4 (helper T), CD6, CD8 (cytotoxic T), CD11b, CD11c (dendritic cells), CD13, CD14 (myelomonocytic cell), CD18, CD27, CD32, CD38, CD43, CD44, CD53, CD66b (granulocyte), CD68 (macrophage), CD69 (maturing NK cell), CD74, CDw78, CD83, CD93, CD117, CD161 (activating NK cell), CD162. All these commercially available antibodies could be used to identify differential expression of immune system cells by immunohistochemistry among normal/benign prostate, PCa of Gleason patterns 3, 4, 5, as well as local and distant metastases. The effective antibody titers for immunohistochemistry of frozen sections have been reported. 6 The immunome review highlighted PCa exhibiting an immunosuppressive TME mainly comprised of MDSC, TAM, and different soluble factors (TGF, IL-6/10/23), frequently leading to immunological tolerance of the tumor. As such, new strategies to overcome this suppressed immune system in PCa will be clinically important, For studies on cell-to-cell interaction (as described in Tools), specific lymphocytes, e.g., CD4+, CD8+, CD45+, from resected normal/benign vs. tumor tissue, or from donor blood samples are co-cultured with CD26+ cancer cells; CD90+ cancer-associated stromal cells (CPstrom) vs. CD49a+ stromal cells (NPstrom). As a substitute, the many LuCaP lines representing adenocarcinoma, non-adenocarcinoma, and small cell carcinoma can be used. The cell types are cultured with or without cell contact, and monitored by transcriptomics and cell appearance. The co-culture is used to demonstrate (1) possible immunosuppressive effect of cancer cells; (2) effect of CPstrom (e.g., via stromal-derived growth factor-1, monocyte chemotactic protein) in altering the gene expression of immune cells (e.g., macrophages), which may enhance tumor cell behavior. CPstrom also differ from NPstrom in chemokine expression of many CXCL molecules.The immunome review also reports on systemic immune response to treatments such as androgen deprivation, which may stimulate CD4+, CD8+ T cells, and macrophages to promote androgen production; androgen receptor signaling inhibition, which could lead to expansion of monocytes; chemotherapy with docetaxel and radiotherapy, which could lead to a pro-inflammatory cascade; checkpoint blockade inhibition with hypoxia, which could induce increases in PDL-1. These reported investigations into the body's immune response post treatment are attempts to explain success or failure of these modalities. Some examples include activation of dendritic cells (plasma cytoid, classical subtypes), myeloid-derived suppressor cells to activate neutrophils, monocytes with inhibition of T cells, B cells, NK cells, CXCL5/CXCR2, IL23 signaling, and other soluble immune related factors -IL-6, TGF-, IL-10 with correlation to Gleason grades, TNF-, INF- with increased tumor cell apoptosis. Appropriate in vitro studies can be designed to test these observations with the responsible immune cell types.