Although dendritic cell (DC) dysfunction in cancer is a well-recognized consequence of cancer-associated inflammation that contributes to immune evasion, the mechanisms that drive this process remain elusive. Here, we show the critical importance of tumor-derived TLR2 ligands in the generation of immunosuppressive IL-10-producing human and mouse DCs. TLR2 ligation induced two parallel synergistic processes that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10 and upregulation of their respective cell surface receptors, which lowered the STAT3 activation threshold. We identified versican as a soluble tumor-derived factor that activates TLR2 in DCs. TLR2 blockade in vivo improved intra-tumor DC immunogenicity and enhanced the efficacy of immunotherapy. Our findings provide a basis for understanding the molecular mechanisms of DC dysfunction in cancer and identify TLR2 as a relevant therapeutic target to improve cancer immunotherapy.
CD200, a type 2 transmembrane molecule of the Ig supergene family, can induce immunosuppression in a number of biological systems, as well as promote increased graft acceptance, following binding to its receptors (CD200Rs). Skin and cardiac allograft acceptance are readily induced in transgenic mice overexpressing CD200 under control of a doxycycline-inducible promoter, both of which are associated with increased intragraft expression of mRNAs for a number of genes associated with altered T cell subset differentiation, including GATA-3, type 2 cytokines (IL-4, IL-13), GITR, and Foxp3. Interestingly, some 12–15 days after grafting, induction of transgenic CD200 expression can be stopped (by doxycycline withdrawal), without obvious significant effect on graft survival. However, neutralization of all CD200 expression (including endogenous CD200 expression) by anti-CD200 mAb caused graft loss, as did introduction of an acute inflammatory stimulus (LPS, 10 μg/mouse, delivered by i.p. injection). We conclude that even with apparently stably accepted tissue allografts, disruption of the immunoregulatory balance by an intense inflammatory stimulus can cause graft loss.
CD200 has been characterized as an important immunoregulatory molecule, increased expression of which can lead to decreased transplant rejection, autoimmunity, and allergic disease. Elevated CD200 expression has been reported to be associated with poor prognosis in a number of human malignancies. We have found that cells of the transplantable EMT6 mouse breast cancer line growing in vitro express low levels of CD200, but levels increase markedly during growth in immunocompetent mice. Similar increased in vivo expression does not occur in NOD-SCID.IL-2(gammar-/-) mice or mice with generalized over-expression of a CD200 transgene. In both mice, tumor growth occurs faster. Altered CD200 expression in control versus transgenic mice is accompanied by reproducible changes in tumor-infiltrating host cells, and altered cell composition in lymph nodes draining the tumor (DLN). Neutralization of expressed CD200 by anti-CD200mAbs leads to decreased tumor growth in immunocompetent mice, with improved detection of cytotoxic anti-tumor immune cells in DLN. Finally, we report that tumor growth in vivo can be monitored by levels of soluble CD200 (sCD200) in serum of tumor-bearing animals.
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