IL-10: master switch from tumor-promoting inflammation to antitumor immunity.
Human cancer is characterized by deficits in antigen-specific immunity and intratumoral CD8(+) T cells. On the other hand, inflammatory macrophages and mediators of chronic inflammation are highly prevalent in patients with late-stage cancer. Intratumoral T-cell deficiency and chronic inflammation have been linked independently to a poor prognosis in patients with cancer, and therapeutic approaches to overcome either pathology separately are in clinical testing. The anti-inflammatory cytokine interleukin (IL)-10 suppresses macrophage and proinflammatory Th17 T-cell responses by inhibiting the inflammatory cytokines IL-6 and IL-12/23. Corroborating the anti-inflammatory action of IL-10, deficiency in IL-10 leads to a stimulation of inflammatory responses and inflammatory bowel disease. The anti-inflammatory role of IL-10 fostered the assumption that IL-10 undermines the immune response to cancer. However, mice and humans deficient in IL-10 signaling develop tumors spontaneously and at high rates. Overexpression of IL-10 in models of human cancer or treatment with a pegylated IL-10 (PEG-IL-10) led to tumor rejection and long-lasting tumor immunity. IL-10 stimulates cytotoxicity of CD8(+) T cells and the expression of IFN-γ in CD8(+) T cells. IL-10-induced tumor rejections are dependent on the expression of IFN-γ and granzymes in tumor-resident CD8(+) T cells and the upregulation of MHC molecules. These findings reconcile earlier clinical data, which showed that recombinant IL-10 increased IFN-γ and granzymes in the blood of treated individuals. PEG-IL-10 is therefore a unique therapeutic agent, which simultaneously stimulates antitumor immunity and inhibits tumor-associated inflammation.
Author's Affiliation: ARMO BioSciences, Redwood City, California.
Martin
M
Oft
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology* / Q000627:therapeutic use; D008264:Macrophages / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology
D016753:Interleukin-10; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D053804:Granzymes