(London, UK) and used as control. vehicle (17 days), whereas non-modified IL-15 or antibodies alone had no significant effects on tumor growth or survival. Histological analysis showed that cyto-IL-15 and cyto-combo increased necrosis and infiltration of natural killer (NK) cells and CD8 T cells in the tumors compared with vehicle and non-modified agents. Overall, the efficacy of cyto-combo was not superior to that of cyto-IL-15 alone. Conclusion We have demonstrated that intratumoral injection of cyto-IL-15 leads to prostate cancer growth delay, induces tumor necrosis and increases survival. Hence, cytotopic modification in combination with intratumoral injection appears to be a Zidebactam sodium salt promising novel approach for prostate cancer immunotherapy. Keywords: IL-15, checkpoint blockade, prostate cancer, cytotopic modification, NK cells Key Points Membrane-localising IL-15, injected directly into prostate tumors in mice induces tumor death and improves mouse survival while circumventing toxicities seen with cytokine immunotherapies administered systemically. This modified IL-15 could have a great impact in treating prostate cancer patients. Introduction Prostate cancer is the Zidebactam sodium salt second leading Zidebactam sodium salt cause of cancer-related death behind lung cancer, and the most common malignancy diagnosed in men.1 Treatments for prostate cancer include surgery, radiation, chemotherapy and androgen deprivation therapy. However, despite the high rates of progression-free survival, almost half of the patients progress to castration-resistant prostate cancer (CRPC).2 It has previously been suggested that prostate cancer can be immunogenic. This is supported by the presence of numerous tumor-associated antigens in the prostate, including prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), as well as tumor infiltrating lymphocytes (TILs), such as CD4 and CD8 T cells, natural killer (NK) cells, dendritic cells (DCs) and macrophages within tumors.3C5 However, the prostate cancer immunogenicity is hampered by the highly immunosuppressive microenvironment, which is probably due to improper functionality of TILs (anergy, exhaustion or senescence) or the presence of regulatory T cells (Tregs).6 High-grade prostate cancer with poorer prognosis has low infiltration of T cells and DCs and high occurrence of Tregs and tumor-associated macrophages;7C9 whereas, elevated infiltration of NK cells within tumors is associated with low risk of prostate cancer progression.10 Immunotherapy, which aims to overcome the immunosuppressive microenvironment and generate or enhance immune responses against tumor cells, has emerged as a promising alternative therapeutic approach for the treatment of prostate cancer. Immunotherapies fall into four categories: adoptive T cell therapy, cancer vaccines, checkpoint inhibitors and cytokines.11 The only FDA-approved vaccine for prostate cancer is Sipuleucel-T (Provenge?), a DC-based vaccine that activates an antitumor response against PAP.12 However, Sipuleucel-T only extends patient survival Rabbit Polyclonal to FPRL2 by few months.13 One of the most studied immune checkpoint targets is cytotoxic T lymphocyte antigen 4 (CTLA-4), which downregulates T cell activation. The anti-CTLA-4 blocking antibody ipilimumab is FDA-approved for the treatment of advanced melanoma and is undergoing clinical trials for prostate cancer. So far, ipilimumab showed no benefit in overall survival, but it slightly improved progression-free survival in metastatic CRPC.14 Programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are also checkpoint targets as their interaction (PD-1/PD-L1) mediates immunosuppression, and thus is a crucial mechanism by which tumors escape immune response.15 To date, the FDA has approved at least six antibodies targeting PD-1/PD-L1, for the treatment of patients with melanoma and solid tumors, such as non-small cell lung cancer and urothelial cancer.16 The anti-PD-1 antibody pembrolizumab is FDA-approved for metastatic melanoma and solid tumors with mismatch Zidebactam sodium salt repair deficiency or microsatellite instability, including metastatic CRPC, for which it has shown a favourable side effect profile.17 However, immunotherapy in prostate cancer has shown less efficacy than in other tumors, probably due to the low somatic mutation burden and suppressive tumor microenvironment.18C20 Therefore, immunotherapies that lead to activation and proliferation of NK and T cells within the tumor microenvironment, used alone or combined with other types of immunotherapies, may.