Tumor cells escape attack from the immune system through various mechanisms, including immune evasion and/or immune suppression. In order to achieve better therapeutic effects using immune modulatory therapy, it is important to study the mechanisms underlying tumor-induced immunosuppression of the tumor-specific T cell response. We found that the growth of various carcinomas induces a significant increase in the numbers of myeloid suppressor cells (MSC) in tumor infiltrating leukocytes (TILs), spleen, and bone marrow of tumor-bearing mice. We hypothesize that MSC suppress the tumor-specific T cell response locally and inactivate tumor-specific T cell response in vivo. The preliminary results support the hypotheses we proposed in our previous submission and indicate that sorted Gr-1+CD115+ MSC isolated from spleen and bone marrow of tumor-bearing mice drastically inhibit IFN-?-producing tumor antigen- activated T cells, significantly reduce expression of IL-2 by T cells, induce expression of IL-10, TGF-?, Foxp3, and Tob, and induce the development of T regulatory cells (Treg) that are anergic and suppressive. Clonal expansion of adoptively transferred tumor antigen-specific T cells occurred during an early stage of tumor growth, but expansion is suppressed by adaptively transferred MSC. At a later time point, tumor-bearing mice developed tolerance associated with Foxp3 and Tob expression in the expanded tumor antigen-specific T cells. Furthermore, adoptive transfer of sorted Gr-1+CD115+ MSC, but not Gr-1-CD115- or Gr-1+CD115- cells, can induce tumor specific anergy and Treg development in recipient tumor-bearing mice. These results provide strong evidence of an immunoregulatory function for MSC in vivo in the establishment of tumor- specific tolerance and the development of Treg. To achieve persistent anti-tumor immunity and to improve the therapeutic effect of immunomodulatory treatments, tumor-induced immunosuppression must be overcome to allow for an effective T cell response.
Three specific aims will be pursued to understand the mechanisms regulating MSC accumulation and the in vivo suppressive function of MSC in tumor bearing mice: 1) to study the mechanisms underlying the accumulation and differentiation of MSC in tumor-bearing mice; 2) to investigate the mechanisms of MSC-mediated tumor specific T cell inactivation in vitro and in vivo; and 3) to prevent the accumulation of MSC and to block their immune inactivation mechanisms, thereby improving immune modulated cancer therapy for treating advanced tumors. Successful completion of these studies will result in a better understanding of the mechanisms underlying tumor-mediated immune suppression by MSC. This information will be utilized as the scientific foundation for the development of a novel therapeutic modality that would counteract the immune suppression associated with advanced malignancy. The ablation of MSC-mediated suppression should significantly augment the efficacy of our immune activation protocol (IL-12 gene delivery plus 4-IBB activation) for patients with advanced cancer. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109322-02
Application #
7227905
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Howcroft, Thomas K
Project Start
2006-05-01
Project End
2011-03-31
Budget Start
2007-05-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$262,923
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
van der Touw, William; Kang, Kyeongah; Luan, Yi et al. (2018) Glatiramer Acetate Enhances Myeloid-Derived Suppressor Cell Function via Recognition of Paired Ig-like Receptor B. J Immunol 201:1727-1734
van der Touw, William; Chen, Hui-Ming; Pan, Ping-Ying et al. (2017) LILRB receptor-mediated regulation of myeloid cell maturation and function. Cancer Immunol Immunother 66:1079-1087
Zhang, Jilu; Mai, Sunny; Chen, Hui-Ming et al. (2017) Leukocyte immunoglobulin-like receptors in human diseases: an overview of their distribution, function, and potential application for immunotherapies. J Leukoc Biol 102:351-360
Wang, Juan; Peng, Liang; Zhang, Ruihua et al. (2016) 5-Fluorouracil targets thymidylate synthase in the selective suppression of TH17 cell differentiation. Oncotarget 7:19312-26
Bronte, Vincenzo; Brandau, Sven; Chen, Shu-Hsia et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150
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 21:4073-4085
Conde, Patricia; Rodriguez, Mercedes; van der Touw, William et al. (2015) DC-SIGN(+) Macrophages Control the Induction of Transplantation Tolerance. Immunity 42:1143-58
Kao, Johnny; Chen, Chien-Ting; Tong, Charles C L et al. (2014) Concurrent sunitinib and stereotactic body radiotherapy for patients with oligometastases: final report of a prospective clinical trial. Target Oncol 9:145-53
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

Showing the most recent 10 out of 31 publications