A growing body of evidence suggests that host immune cells with a suppressive phenotype pose a significant hurdle to successful immune enhancing therapy for cancer. Among the suppressor cells, T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been shown to increase significantly in hosts with advanced malignancies. Previously, we found that the growth of various carcinomas induced a significant increase in the numbers of MDSC and Treg in tumor, spleen, and bone marrow. More interestingly, we have demonstrated that MDSC can mediate suppression of the tumor-specific T-cell response through the induction of T-cell anergy and the development of Treg in tumor-bearing mice. These results provide strong evidence of the in vivo immune suppressive functions of MDSC and Treg in tumor-bearing host. To achieve persistent anti-tumor immunity and to improve the efficacy of immunomodulatory therapy, tumor-induced immune suppression must be investigated and overcome. Our studies indicate that targeted pharmacological disruption of tyrosine kinase signaling through the use of a small molecule inhibitor (sunitinib malate; Sutent(r)) can prevent the accumulation of MDSCs and the suppressive activity of Treg, thereby improving the efficacy of immune-based therapy. We have found that leukocyte subsets required for the regulation of inflammatory response vs. immune suppression in the tumor microenvironment can be modulated by sunitinib treatment. We hypothesize that disruption of the receptor tyrosine kinase activation pathway may not only revert Treg suppressive function and Foxp3 gene expression but also stimulate Th17 and Th1 inflammatory responses.
Three specific aims will be pursued: 1) To study the molecular mechanisms underlying the regulatory effect of tyrosine kinase inhibitors (TKIs) on Treg signaling and function in vitro and in vivo; 2) To study the effect of TKI on the conversion of Treg into Th17 and/or Th1; 3) To study the effect of TKI, on human Treg and in TKI treated cancer patients, and the underlying molecular mechanisms. Studies of the cellular and molecular mechanisms of action utilized by sunitinib malate are critically important for future clinical translation. Successful completion of these studies will result in a better understanding of the mechanisms of action employed by sunitinib to alter the tumor microenvironment and result in immune conversion and may lead to the discovery of novel and specific targets that can be used to combat the immune suppression associated with advanced malignancies. The ablation of immune suppression should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic cancer.
The goal of this project includes 1) Identify the direct targets and regulation mechanisms of Sutent in CD4+CD25+FoxP3+ T regulatory cells; 2) Identify tyrosine kinase inhibitors that have a similar or stronger effect than Sutent; 3) Study the mechanisms underlying the conversion of T regulatory cells to other CD4 lineages mediated by Sutent; 4) Study the effect of Sutent on human T regulatory cells in cancer patients.
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