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, that plays 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 anti-tumor impact of IL-32 gene therapy, we treated BALB/c mice bearing established s.c. CMS4 sarcomas with intratumoral (i.t.) injections of syngenic dendritic cells (DC) engineered to express human IL-32β cDNA (i.e. DC.IL32). While ectopic expression of IL-32β by DC resulted in only modest phenotypic changes in these antigen presenting cells (APC), 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 (i.e. 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 (MDSC) and CD31⁺ blood vessels.