The Role Of CD4^low?HLA-G⁺? T Cells In CRPC Occurrence And Targeted Therapy For Prostate Cancer

Androgen deprivation therapy?ADT?is a main treatment for prostate cancer?PCa?,but the disease recurs and becomes castration-resistant in nearly all patients.Recent emerging data implicate that immune cells are involved in the formation of CRPC and in particular,T cells are expanded in PCa patients and mouse models shortly after androgen deprivation.However,whether and which of the T cell subtypes play an active,important role during the development of CRPC is unknown.Here we identified a novel population of CD4^lowHLA-G⁺T cells that undergo significant expansion in PCa patients after ADT.In mouse PCa models,a similar CD4^lowow T cell population becomes noticeable at the early stage of CRPC formation.Phenotypic characterizations defined these cells as IL-4-expressing T_H17 cells,a cell population associated with CRPC formation in patients,and essential for the development of CRPC in mouse models.Mechanistically,the CD4^low?HLA-G⁺?T cells drove androgen-independent growth of prostate cancer cells by modulating the activity and migration of CD11b^lowF4/80^hii macrophages.Furthermore,following androgen deprivation,elevated PGE₂-EP2 signaling inhibited the expression of CD4 in thymocytes,and subsequently induced the polarization of CD4^lowow naive T cells towards IL-4-expressing T_H17 cells via up-regulation of IL23R.Therapeutically,inactivating PGE₂ signaling with celecoxib,a selective COX-2 inhibitor,at the time when CD4^low?HLA-G⁺?T cells appeared,but not immediately following androgen deprivation,dramatically suppressed the formation of CRPC.Collectively,our current study indicates that an unusual population of CD4^low?HLA-G⁺?T cells is essential for the formation of CRPC and points to a new therapeutic avenue of combining ADT with PGE₂ inhibition for the treatment of prostate cancer.