Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Abstract

The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, phenotype, and functions of NK cells infiltrating control and tumor prostate tissues. NK cell infiltrates in prostate tissues were mainly CD56 (NCAM1)-positive and displayed an unexpected immature, but activated, phenotype with low or no cytotoxic potential. Furthermore, we show that TGFb1 (TGFB1) is highly secreted into the prostate environment and partly mediates the immunosuppressive effects on NK cells. In addition to this basal level of immunotolerance to NK cells, the prostate environment became further resistant to NK cell-mediated immunity upon cancer cell infiltration. Coculture experiments revealed that prostate cancer cells induced the expression of inhibitory receptor (ILT2/ LILRB1) and downregulated the expression of activating receptors NKp46 (NCR1), NKG2D (KLRK1), and CD16 (FCGR3) by NK cells, thus preventing their recognition of tumor cells. Notably, blood levels of NKp46 were also decreased in prostate cancer patients and were inversely correlated with levels of prostate-specific antigen, the main prognostic factor in prostate cancer. Our study shows that a strong immunosuppressive environment impairs NK cell function at multiple levels in prostate cancer and provides a rationale for the design of therapies that restore NK cell efficiency in the prostate tumor microenvironment. Cancer Res; 76(8); 2153-65. Ó2016 AACR.

Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels

“…In this study, we focused on the role of intracellular IL‐6 signaling in developing the resistance of PCa cells to NK cell‐mediated cytotoxicity. It was previously suggested that an immunosuppressive environment impairs NK cell function at multiple levels in PCa (Pasero et al ., ). IL‐6 can be secreted by other types of cells in the tumor microenvironment (TME) including macrophages, endothelial cells, and bone marrow mesenchymal cells.…”

“…In addition to the upregulation of PD‐L1, the downregulation of NKG2D‐activating ligands such as UL16 binding protein 1 (ULBP1), ULBP2, ULBP3, major histocompatibility complex class I chain‐related molecules A and B (MICA and MICB) was reported to be another pathway for tumor cells to escape from NK cell‐mediated cytotoxic actions (Nausch and Cerwenka, ). It was also suggested that the downregulated NKG2D in NK cells prevented NK cell recognition by tumor cells (Pasero et al ., ). In addition, Liu et al .…”

Cellular determinants and microenvironmental regulation of prostate cancer metastasis

“…However, recent detection of tissue tolerance mechanisms against NK cells further implicates the presence of a strong immunosuppressive environment in PCa. For instance, NK cells infiltrating the prostate gland display an immature phenotype with low or no cytotoxic potential, and PCa cells may also induce the expression of NK inhibitory receptors and downregulate the expression of NK activating receptors [71]. The function of mast cells (MCs) in mPCa is clearly determined by the microenvironment.…”

Understanding the epigenetic regulation of tumours and their microenvironments: opportunities and problems for epigenetic therapy

“…A high level of NK cell infiltration correlates with a favourable prognosis in numerous cancer types . However, the immunosuppressive tumour microenvironment can also impair NK cell cytotoxicity by increasing the numbers of MDSCs or other immunosuppressive cells .…”