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 in tumor, spleen, and bone marrow of tumor-bearing mice. More interestingly, we have demonstrated that MDSC can mediate the suppression of the tumor-specific T-cell response through the induction of T-cell anergy and the development of Treg in vitro and in tumor-bearing mice. These results provide strong evidence of an in vivo immunoregulatory function of MDSC in the establishment of tumor-specific tolerance and the development of Treg in tumor-bearing hosts. To achieve persistent anti- tumor immunity and to improve the therapeutic effect of immunomodulatory treatments, the tumor-induced immunosuppression must be overcome and investigated. Our preliminary results indicate that ckit ligand (stem cell factor) expressed by tumor cells may be required for MDSC accumulation in tumor bearing mice and that blocking the ckit ligand/ckit receptor interaction can prevent the development of Treg and reverse tolerance induced by MDSC. We hypothesize that: 1) Targeted pharmacological disruption of c-kit receptor signaling by using small molecule inhibitors can prevent the accumulation of MDSCs and Treg suppression, thereby increasing the therapeutic efficacy of immune-based therapy;2) Disruption of ckit receptor tyrosine kinase activation pathway can stimulate Th1 responses and prevent T-cell tolerance and Th2 polarization in mice with advanced malignancies;3) Leukocyte subsets required for the establishment of immune tolerance in tumor microenvironment can be modulated by blocking the signaling pathways of ckit.
Three specific aims will be pursued: 1) To study the effect of receptor tyrosine kinase inhibitors on MDSC accumulation, MDSC-mediated Treg development, and suppressive function Treg in mice with large tumor burdens;2) To study the underlying mechanisms and cell types that are involved in the immune tolerance, which can be disrupted by class III receptor tyrosine kinase inhibitors in advanced murine colon tumor models;3) To study the effect of small molecule inhibitors on the expansion of MDSC, Treg, and immune tolerance in treated cancer patients. Successful completion of these studies will result in a better understanding of the mechanisms of action by these small compounds and immune tolerance, which may lead to the discovery of novel targets for the intervention in tumor-associated immunosuppression. The information will be utilized as the scientific foundation for the development of a novel therapeutic modality that can counteract the immune suppression associated with advanced malignancy. The ablation of immune tolerance should significantly augment the efficacy of existing immune-based therapies for treatment of advanced metastatic colorectal carcinomas.
The goal of this project is 1) To investigate whether pharmacological inhibition of signaling of tumor factors can prevent MDSC accumulation and can intervene with the suppressive activities of MDSC;(2) To identify the underlying mechanisms and cytokines and cell subsets that are involved in small molecule-mediated blockade of Treg expansion and reversion of T-cell tolerance. The therapeutic potential of modulating the suppressive functions through the use of receptor tyrosine kinase inhibitors to complement existing immune based strategies for treating advanced large tumors will be evaluated;(3) To study the effect of tyrosine kinase inhibitors (Gleevec and Sutent) on MDSC suppressive activities and anti-tumor responses in cancer patients.
|Chen, Hui-Ming; Ma, Ge; Gildener-Leapman, Neil et al. (2015) Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy. Clin Cancer Res 21:4073-85|
|Conde, Patricia; Rodriguez, Mercedes; van der Touw, William et al. (2015) DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity 42:1143-58|
|Eisenstein, Samuel; Chen, Shu-Hsia; Pan, Ping-Ying (2014) Immune cells: more than simple carriers for systemic delivery of oncolytic viruses. Oncolytic Virother 3:83-91|
|Shen, Jin; Chen, Xiaojuan; Wang, Zhenxing et al. (2014) Downregulation of CD40 expression contributes to the accumulation of myeloid-derived suppressor cells in gastric tumors. Oncol Lett 8:775-780|
|Wang, Ying; Chen, Kun; Wu, Zhiyuan et al. (2014) Immunizations with hepatitis B viral antigens and a TLR7/8 agonist adjuvant induce antigen-specific immune responses in HBV-transgenic mice. Int J Infect Dis 29:31-6|
|Eisenstein, Samuel; Coakley, Brian A; Briley-Saebo, Karen et al. (2013) Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 73:5003-15|
|Ochando, Jordi C; Chen, Shu Hsia (2012) Myeloid-derived suppressor cells in transplantation and cancer. Immunol Res 54:275-85|
|Ma, Ge; Pan, Ping-Ying; Eisenstein, Samuel et al. (2011) Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells. Immunity 34:385-95|
|Meseck, Marcia; Huang, Tiangui; Ma, Ge et al. (2011) A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer. J Immunother 34:175-82|
|Kao, Johnny; Ko, Eric C; Eisenstein, Samuel et al. (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77:12-9|
Showing the most recent 10 out of 14 publications