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Autocrine Production of IL-10 Mediates Defective IL-12 Production and NF-B Activation in Tumor-Associated Macrophages¹

Antonio Sica^2,*, Alessandra Saccani^*, Barbara Bottazzi^*, Nadia Polentarutti^*, Annunciata Vecchi^*, Jo Van Damme and Alberto Mantovani^*,

^* Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy; Department of Biotechnology, University of Brescia, Brescia, Italy; and Rega Institute for Medical Research, University of Leuven, Leuven, Belgium

IL-12 is a central cytokine in the activation of inflammation and immunity and in the generation of Th1-type responses. Tumor-associated macrophages (TAM) from mouse and human tumors showed defective production of IL-12. Defective IL-12 production was associated with lack of p50/p65 NF-B activation. TAM produced increased amounts of the immunosuppressive cytokine IL-10. Abs against IL-10 restored the defective capacity of TAM to produce IL-12. Our data suggest that during tumor growth an IL-10-dependent pathway of diversion of macrophage function can be activated into the tumor microenvironment and results in the promotion of the IL-10⁺ IL-12^- phenotype of TAM. Blocking IL-10, as well as other immunosuppressive cytokines present in the tumor microenvironment, such as TGF-, may complement therapeutic strategies aimed at activating type I antitumor immune responses.