On The Role Of IL-10 In Anti-tumor Immunity

Studies using IL-10 reporter mice have revealed that CD8+ T lymphocytes and myeloid lineage of cells are the major sources of IL-10. However the roles of CD8+ T cell and myeloid cell-derived IL-10 in tumor immunity are controversial and are poorly understood. Here we have used a series of genetic models to investigate the impacts of IL-10 on the functions of tumor specific cytotoxic T lymphocytes (CTL) and tumor associated myeloid cells (TAMCs). The overall effects of IL-10 on tumor microenvironment formation and tumor immunity are also evaluated.We injected plasmacytoma J558 cells into IL-10-/- BALB/c mice and wild type BALB/c mice and found that J558 tumors grew much faster in IL-10-/- mice than in wild type mice. The tumor growth delay in wild type BALB/c mice was caused by adaptive immunity since the same J558 tumor grew similarly in IL-10-/- RAG-2-/- and IL-10+/+ RAG-2-/- mice that are deficient for T and B lymphocytes. We found that more CD8+ and CD4+ T cells infiltrated into J558 tumors in wild type mice than in IL-10-/-mice. Moreover, CD8+ T cells from tumors in wild type mice produced more IFN-y than that in IL-10-/- mice. In tumor-bearing RAG-2-/- mice, IL-10-deficient P1CTL transgenic T cells (CD8+ T cells specific for a tumor antigen P1A) proliferated poorly and were less efficient in rejecting established tumors compared with their wild type counterparts. Thus, IL-10-deficient CD8+ T cells are intrinsically defective in anti-tumor responses.Studies have revealed that TAMCs in tumor-bearing mice produce high amount of IL-10. However the roles of TAMC-derived IL-10 in tumor immunity are poorly understood. Here we show that IL-10 blockade or IL-10-deficiency resulted in reduced ability of TAMCs to suppress the proliferation of tumor antigen P1A-specific CD8+ T ceils. IL-10-/- RAG-2-/- and IL-10+/+ RAG-2-/- mice bearing large tumor burdens have similar TAMCs populations, however, adoptively transferred tumor antigen specific CD8+ T cells expanded more efficiently in IL-10-/-RAG-2-/- mice than in IL-10+/+RAG-2-/- mice. Moreover, TAMCs from IL-10-/- mice produced more inflammatory cytokines compared with TAMCs from wild type mice, and CTL adoptive transfer therapy prevented tumor evasion in IL-10-/-RAG-2-/- mice but not in IL-10+/+RAG-2-/- mice. Thus, IL10-deficincy converted TAMCs from tumor-promoting, immune suppressive cells into anti-tumor immune effectors.We have also evaluated the roles of IL-10 on tumor microenvironment formation. We found that tumors in IL-10 deficient mice contained less CD8+, CD4+ T cells and TAMCs and had more blood vessels formation compared with that of wild type mice. However, we found that the IL-10-deficient tumor microenvironments were more inflammatory, as reflected by more IL-6, TNF-a and IL-17 expression. Thus, IL-10-deficiency induced a series of changes in tumor microenvironment, which lead to faster tumor growth in IL-10-/- mice than in wild type mice.Taken together, we have found two opposing roles of IL-10 in tumor immunity. First, we have found that IL-10-deficient CD8+ T cells are intrinsically defective in anti-tumor response. Second, IL-10 is a converter of tumor associated myeloid cells, and IL-10-deficincy converted TAMCs from tumor-promoting, immune suppressive cells into anti-tumor immune effectors. However, the overall inflammatory environment in IL-10-deficient mice and the intrinsic defects of IL-10-deficient CTLs resulted in less CTL accumulation in tumors, leading to faster tumor growth in IL-10-/- mice.