Regulation of the anti-tumor immune response by host Stat1 and Stat6.

摘要

Our laboratory has previously observed that Stat1-deficient mice fail to reject an immunogenic tumor, which was correlated with impaired generation of tumor-specific CTL. Bone marrow chimera experiments revealed that Stat1-expression in the hematopoietic compartment was required. Allogeneic in vitro MLR experiments indicated that Stat1-/- T cells are intrinsically able to differentiate into effector CTL. These observations prompted investigation into the role for Stat1 in non-T hematopoietic cells, which focused attention on APCs. Quantitative characterization of the T cell response to tumor in vivo by peptide-specific ELISPOT and MHC tetramer analysis revealed a marked diminution in the numbers of tumor-specific CD8+ T cells detected from Stat1-/- mice ex vivo. Additionally, adoptive transfer experiments with CFSE-labeled tumor-specific CD8+ T cells demonstrated that host Stat1 expression was required for robust proliferation of CD8+ T lymphocytes in response to a tumor challenge. Collectively, our in vitro and in vivo experiments are most consistent with a model in which Stat1 is required in non-T hematopoietic cells to carry out optimal cross-priming of CD8+ T cells against tumor-associated antigens in vivo.;As type 1 T cell responses may be optimal for tumor rejection in vivo, failure to reject tumors may be due to poor generation of a type 1 phenotype, through a dominant influence of the type 2-promoting cytokines IL-4 and/or IL-13. This hypothesis was tested by implanting syngeneic tumors into Stat6-deficient mice. In contrast to progressive growth of these tumors in wild-type mice, Stat6-/- mice spontaneously rejected such a tumor challenge. Rejection was accompanied by augmented tumor-specific IFN-gamma production and CTL activity. These results suggest that pharmacologic inhibition of Stat6 signaling could potentiate anti-tumor immunity in vivo.;Although type 1 and type 2 cytokines have traditionally been thought of in the context of CD4+ helper T cell differentiation, application of this paradigm to tumor immunology has yielded interesting insights into the requirements for in vivo tumor rejection. Additionally, work to elucidate the mechanisms by which host Stat1 and Stat6 regulate anti-tumor immunity has revealed potentially novel roles for these molecules in shaping T cell responses.