Fig. 2

Interleukin-12 plays multiple roles within the local tumor microenvironment to sustain an anti-tumor response but malignant cells evolve mechanisms to suppress the local activity of IL12. a IL12 is secreted by macrophages and dendritic cells and acts on Natural Killer (NK) cells, CD4+ T helper cells, and CD8+ cytotoxic T cells to promote an anti-tumor immune response by enhancing antibody-dependent cell-mediated cytotoxicity and cytotoxic T cell activity. Effective anti-tumor immunity is also associated with local proliferation of CD8+ T cells within the tumor microenvironment [113]. Immune cell proliferation also diminishes the cellular response imprinted by IL12 stimulation [48], which suggests that local IL12 may help sustain the cytotoxic activity of CD8+ T cells. b As a result of somatic evolution, the B16F0 model for melanoma has evolved multiple mechanisms to suppress the bioactivity of IL12. B16F0 cells over express one component of the IL12 receptor, IL12RB2, to form a local cytokine sink (light blue whiskers on malignant cells) B16F0 cells secrete WISP1 (red cloud), which is a paracrine inhibitor of IL12 bioactivity, and exosomes (yellow circles). B16F0 exosomes contain IL12RB2, which can contribute to the cytokine sink, and deliver an immunosuppressive payload to suppress the proliferation of CD8+ T cells. As B16F0 exosomes are around 160 nm in size, they are likely to accumulate within the local tumor microenvironment