Combined immunotherapy for advanced prostate cancer: Empowering the T cell army

Prostate cancer (PCa) is the second leading cause of death among men worldwide. Androgen signaling plays key roles in PCa progression [1], and so far available therapeutic agents mainly target androgens or androgen receptor (AR) [2]. However, the patients receiving these treatments often recurs with progression to castration resistant prostate cancer (CRPC) [3]. Metastatic CRPC (mCRPC) is the advanced and lethal stage of PCa [4]. Recent advances in the field show that immune checkpoint blockade (ICB) is the paramount choice for targeting many types of cancers including PCa [4e6]. ICB generates effective therapeutic response across certain cancers [5], whereas it failed to improve overall survival of patients with mCRPC [7]. To address this challenge, one recent studyby Luand colleagues [8] has demonstrated an ICB approach combined with targeted drugs for myeloid-derived immune suppressive cells (MDSCs), thereby enforcing the T cells to combat mCRPC tumor cells [8]. The authors have shown that, MDSCs are recruited to tumor microenvironment (TME) and exert immune suppressive impact on Tcells. MDSCs immune suppression can be prevented using targeted drugs combined with ICB. The landmark strategy introduced by authors is a step towards solving the problem of drug resistance and ICB evasion in PCa and its progression to mCRPC. Previous studies revealed that ICB improves overall survival in melanoma. In ICB antibodies against cytotoxic-Tlymphocyte-associated protein 4 (CTLA4) and programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1), target the surface CTLA4 and PD1/PD-L1 receptors thereby stimulating and inhibiting the production of cytokines, interleukin-2 (IL-2) and interferon-g (IFN-g) respectively [5,9]. IL-2 production and IFN-g inhibition, increase T cell proliferation, restore activated T cell response and reduce immunosuppression, cumulatively activating the immune response against tumor cells [9]. However, mCRPC shows resistance against ICB, due to MDSCs [10] that are major component of TME with immunosuppressive activity [11]. Mouse (Pten / and smad4 / ) model of PCa tumors indicated that chemokine CXCL5 recruits MDSCs to TME, which enables PCa tumor initiation and progression [10]. In this current study, Lu and colleagues developed a chimeric mCRPC mouse model (CPPSML) for effective testing of combination immunotherapy. CPPSML chimericmousewith