Hence, CD4low T cells regulate the activities and migration of TAMs by IL-4 and IL-17 to promote androgen-independent growth of prostate cancer cells

Hence, CD4low T cells regulate the activities and migration of TAMs by IL-4 and IL-17 to promote androgen-independent growth of prostate cancer cells. PGE2-EP2 signaling promotes the differentiation and polarization of CD4low T cells To explore the mechanism responsible for production of CD4low T cells, CD4+ T cells in the peripheral (TdLN and spleen) and central (thymus) lymphoid organs of CRPC TRAMP mice were analyzed by flow cytometry. (580K) GUID:?649BFAA3-F5DC-4B9E-B38C-7DF9C04515AF Supplementary information, Figure S24 41422_2018_89_MOESM24_ESM.pdf (279K) GUID:?17F1E31A-385D-42E1-B83D-C64D15393947 Supplementary information, Table S1 41422_2018_89_MOESM25_ESM.pdf (62K) GUID:?BBA6DDFA-B80D-48D0-B74D-4799485EB621 Supplementary information, Table S2 41422_2018_89_MOESM26_ESM.pdf (249K) GUID:?DB51D9B8-3F54-4787-9436-66717462D5E7 Supplementary information, Table S3 41422_2018_89_MOESM27_ESM.pdf (617K) GUID:?DB546C1D-1AB5-4A2E-804D-566BE021A734 Supplementary information, Data S1 41422_2018_89_MOESM28_ESM.pdf (72K) GUID:?24DE5B2C-5EF7-4874-9302-2B11505FA53B Abstract Androgen deprivation therapy (ADT) is a main treatment for prostate cancer (PCa) but the disease often recurs and becomes castration-resistant in nearly all patients. Recent data implicate the involvement of immune cells in the development of this castration-resistant prostate cancer (CRPC). In particular, T cells have been found to be expanded in both PCa patients and mouse models shortly after androgen deprivation. However, whether or which of the T cell subtypes play an important role during the development of CRPC is unknown. Here Cyclopropavir we identified a novel population of CD4lowHLA-G+ T cells that undergo significant expansion in PCa patients after ADT. In mouse PCa models, a similar CD4low T cell population expands during the early stages of CRPC onset. These cells are identified as IL-4-expressing TH17 cells, and are shown to be associated with CRPC onset in patients and essential for the development of CRPC in mouse models. Mechanistically, CD4lowHLA-G+ T cells drive androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11blowF4/80hi macrophages. Furthermore, following androgen deprivation, elevated PGE2-EP2 signaling inhibited the expression of CD4 in thymocytes, and subsequently induced the polarization of CD4low na?ve T cells towards the IL-4-expressing TH17 phenotype via up-regulation of IL23R. Therapeutically, inactivating PGE2 signaling with celecoxib at a time when CD4lowHLA-G+ T cells appeared, but not immediately MYH11 following androgen deprivation, dramatically suppressed the onset of CRPC. Collectively, our results indicate that an unusual population of CD4lowHLA-G+ T cells is essential for the development of CRPC and point to a new therapeutic avenue of combining ADT with PGE2 inhibition for the treatment of prostate cancer. Introduction Prostate cancer is the Cyclopropavir most commonly diagnosed cancer and the third leading cause of cancer-related deaths among men in western countries.1 Although androgen deprivation therapy (ADT), the main treatment for prostate cancer, is initially effective for most patients, the disease often recurs and becomes castration-resistant within 18 to 24 months.2,3 The mechanism underlying this castration-resistance remains poorly understood. 4 Previous studies in mice and humans have reported that Cyclopropavir androgen ablation may activate thymic regeneration, elevate the absolute numbers of peripheral T cells, particularly CD4+ T cells, and enhance the responsiveness of cytotoxic T lymphocytes (CTLs) to specific-antigen stimulation.5C7 Consistently, androgen ablation was found to remove the CD4 T cell tolerance to prostate tumor-restricted antigen, which allows these cells to expand and produce effector cytokines after vaccination with prostate-specific antigen.8 However, whether androgen ablation can trigger anti-tumor immunity still Cyclopropavir remains controversial. For example, recent studies have revealed that several types of immune cells, including T, B, NK, and myeloid cells, infiltrate into the prostate tumor microenvironment after androgen ablation, which promotes castration-resistance of prostate cancer by activating IKK- and STAT3 in the tumor cells.9,10 The dual roles of immune cells in the progression of prostate cancer after ADT indicate that there might be a conversion from an anti-tumor to a pro-tumor immune response during the occurrence of CRPC. However, what drives this transition is still unknown. Phenotypic and functional plasticity is a hallmark of several types of immune cells in the tumor microenvironment, especially CD4 T helper.