Tumor growth is associated with a profound alteration of myelopoiesis, leading to recruitment of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs). Analyzing the cytokines affecting myelo-monocytic differentiation produced by various experimental tumors, we found that GM-CSF, G-CSF, and IL-6 allowed a rapid generation of MDSCs from precursors present in mouse and human bone marrow (BM). BM-MDSCs induced by GM-CSF+IL-6 possessed the highest tolerogenic activity, as revealed by the ability to impair the priming of IFN- -producing CD8+ T cells upon in vivo adoptive transfer. Moreover, adoptive transfer of syngeneic, GM-CSF+IL-6-conditioned MDSCs to diabetic mice transplanted with allogeneic pancreatic islets resulted in long term acceptance of the allograft and correction of the diabetic status. Cytokines inducing MDSCs acted on a common molecular pathway. Immunoregulatory activity of both tumor-induced and BM-derived MDSCs was entirely dependent on C/EBP transcription factor, a key component of the emergency myelopoiesis triggered by stress and inflammation. Adoptive transfer of tumor antigen-specific CD8+ T lymphocytes resulted in therapy of established tumors only in mice lacking C/EBP in myeloid compartment. These data unveil another link between inflammation and cancer and identify a novel molecular target to control tumor-induced immune suppression.
Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor.
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The effectiveness of new cancer therapies such as checkpoint blockade and adoptive cell transfer of activated anti-tumor T cells requires overcoming immunosuppressive tumor microenvironments. We found that the activation of tumor-infiltrating myeloid cells to produce local nitric oxide is a prerequisite for adoptively transferred CD8+ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to Tip-DCs or nitric oxide- and TNF-producing dendritic cells. The nitric oxide-dependent killing was tempered by coincident arginase 1 expression, which competes with iNOS for arginine, the substrate for nitric oxide production. Depletion of immunosuppressive CSF-1R-dependent arginase 1+ myeloid cells enhanced nitric oxide-dependent tumor killing. Tumor killing via iNOS was independent of the microbiota but dependent on the CD40-CD40L pathway and, in part, lymphotoxin alpha. We extended our findings in mice to uncover a strong correlation between iNOS, CD40 and TNF expression and survival in colorectal cancer patients. Our results identify a network of anti-tumor targets to boost the efficacy of cancer immunotherapies.
T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells.
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To investigate the genes differentially induced by c-FLIP up-regulation by lentivirus infection in monocytes from healthy donors
Induction of immunosuppressive functions and NF-κB by FLIP in monocytes.