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Heterogeneous interleukin-15 inducibilities in murine B16 melanoma and RM-1 prostate carcinoma by interferon-alpha treatment.

ABSTRACT: Long-term treatment of mouse cancer cells with interferon-alpha (IFN-alpha) converts parental B16 melanoma cells to B16alpha vaccine cells. Inoculation of syngeneic mice with UV-irradiated B16alpha vaccine cells triggers immunity to the parental B16 tumor that is mediated by host macrophages, T cells, and NK cells. Lymph node cells from mice inoculated with irradiated B16alpha vaccine cells, but not with irradiated parental cells, proliferate when cultured in vitro, suggesting long-term in vivo activation of lymphoid cells. Both IL-15 mRNA and IL-15 protein are highly induced in B16alpha vaccine cells. The bulk of the induced IL-15 is shown to be cell-associated, either cytoplasmic or membranous. The current study investigated the feasibility of applying the B16alpha vaccination protocol to generate a cancer vaccine against murine RM-1 prostate carcinoma. In comparison to B16alpha vaccine cells, long-term IFN-alpha-treated RM-1 cells (RM-1alpha vaccine cells) showed significant IL-15 mRNA induction but relatively low IL-15 protein up-regulation. When UV-irradiated, a 3-fold increase in intracellular IL-15 was observed in RM-1alpha vaccine cells, suggesting UV damage may have negated a possible control mechanism for IL-15 synthesis. Efficacy of in vivo vaccination of syngeneic mice with UV-irradiated RM-1alpha and B16alpha vaccine cells showed correlation between high IL-15 level and high vaccine efficacy in B16alpha cells compared to low IL-15 level and low vaccine efficacy in RM-1alpha cells. This supports the concept that the induction of IL-15 in tumor cells can be useful for creating whole-cell cancer vaccines.

SUBMITTER: Wu TG

PROVIDER: S-EPMC3096523 | biostudies-other | 2009 Nov

REPOSITORIES: biostudies-other

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Project description:Background:The prostate cancer microenvironment is highly immunosuppressive; immune cells stimulated in the periphery by systemic immunotherapies will be rendered inactive once entering this environment. Immunotherapies for prostate cancer need to break this immune tolerance. We have previously identified interleukin-15 (IL-15) as the only cytokine tested that activates and expands immune cells in the presence of prostate cancer cells. In the current study, we aimed to identify a method of boosting the efficacy of IL-15 in prostate cancer. Methods:We engineered, by conjugation to a myristoylated peptide, a membrane-localising form of IL-15 (cyto-IL-15) and the checkpoint inhibitor antibodies cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) (cyto-abs) to enable them to bind to cell surfaces by non-specific anchoring to the phospholipid bilayer. The efficacy of these agents was investigated by intratumoral administration either alone (cyto-IL-15 or cyto-abs) or in combination (cyto-combo) in subcutaneous TRAMP-C2 prostate tumors in C57BL/6J mice and compared with their non-modified equivalents in vivo. Following the survival endpoint, histological analyses and RNA sequencing were performed on the tumors. Results:Intratumoral injection of cyto-IL-15 or cyto-combo delayed tumor growth by 50% and increased median survival to 28 and 25 days, respectively, compared with 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 promising novel approach for prostate cancer immunotherapy.

Project description:UnlabelledIn chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8(+) T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-?) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8(+) immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-?- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-?, which, given together, constitute a potent approach to significantly enhance the CD8(+) T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions.ImportanceWith 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not very effective and/or need to be administered for life. The unprecedented efficacy of the strategy described in our paper may offer an alternative and is relevant for a broad spectrum of readers because of its clear translational importance to other chronic viral infections in which a hyporesponsive antigen-specific T cell repertoire prevents clearance of the pathogen.

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Heterogeneous interleukin-15 inducibilities in murine B16 melanoma and RM-1 prostate carcinoma by interferon-alpha treatment.

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