Therapeutic effectiveness of intratumorally delivered dendritic cells engineered to express the pro-inflammatory cytokine, interleukin (IL)-32

摘要

Interleukin-32 (IL-32) is a pro-inflammatory cytokine conditionally produced by T cells, natural killer (NK) cells, monocytes, epithelial cells and keratinocytes, which has an important role in host resistance against infectious disease. Interestingly, elevated levels of IL-32 transcripts in fine needle aspirates of tumor tissue have also been correlated with objective clinical responses in cancer patients receiving immunotherapy. To evaluate the antitumor impact of IL-32 gene therapy, we treated BALB/c mice bearing established subcutaneous CMS4 sarcomas with intratumoral (i.t.) injections of syngenic dendritic cells (DCs) engineered to express human IL-32β complementary DNA (that is, DC.IL32). Although ectopic expression of IL-32β by DC resulted in only modest phenotypic changes in these antigen-presenting cells, DC.IL32 produced higher levels of IL-12p70 than control DC. DC.IL32 were more potent activators of type-1 T-cell responses in vitro and in vivo, with i.t. administration of DC.IL32 leading to the CD8+ T-cell-dependent (but CD4+ T-cell- and NK cell-independent) suppression of tumor growth. Effective DC.IL32-based therapy promoted infiltration of tumors by type-1 (that is, CXCR3+VLA-4+GrB+) CD8+ T cells and CD11b+CD11c+ host myeloid DC, but led to reductions in the prevalence of CD11b+Gr1+ myeloid-derived suppressor cells and CD31+ blood vessels.