Myeloid suppressor cell-mediated immune suppression of tumor specific T cells

Summary

Principal Investigator: Shu Hsia Chen
Affiliation: Mount Sinai School of Medicine
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): 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. [unreadable] [unreadable]
Funding Period: 2006-05-01 - 2011-03-31
more information: NIH RePORT

Top Publications

  1. pmc Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy
    Samuel Eisenstein
    Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cancer Res 73:5003-15. 2013
  2. doi The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies
    Junko Ozao-Choy
    Departments of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA
    Cancer Res 69:2514-22. 2009
  3. ncbi Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells
    Zuping Zhou
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
    Stem Cells 28:620-32. 2010
  4. pmc Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells
    Ge Ma
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 13 02, New York, NY 10029 6574, USA
    Immunity 34:385-95. 2011
  5. pmc A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer
    Marcia Meseck
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Immunother 34:175-82. 2011
  6. doi Myeloid-derived suppressor cells prevent type 1 diabetes in murine models
    Bingjiao Yin
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Immunol 185:5828-34. 2010
  7. pmc Myeloid-derived suppressor cells: natural regulators for transplant tolerance
    Peter Boros
    Recanati Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY, USA
    Hum Immunol 71:1061-6. 2010
  8. pmc Targeting immune suppressing myeloid-derived suppressor cells in oncology
    Johnny Kao
    Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, United States
    Crit Rev Oncol Hematol 77:12-9. 2011
  9. pmc Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer
    Ping Ying Pan
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
    Cancer Res 70:99-108. 2010
  10. pmc Advancements in immune tolerance
    Ping Ying Pan
    Department of Gene and Cell Medicine, Mount Sinai School od Medicine, New York, NY 10029, USA
    Adv Drug Deliv Rev 60:91-105. 2008

Scientific Experts

  • Ping Ying Pan
  • P Boros
  • Johnny Kao
  • Ge Ma
  • Shu Hsia Chen
  • Celia M Divino
  • Samuel Eisenstein
  • Marcia Meseck
  • Zuping Zhou
  • Bingjiao Yin
  • George X Wang
  • Junko Ozao-Choy
  • Bo Huang
  • Hui Ming Chen
  • Celia Divino
  • Savio Woo
  • Brian A Coakley
  • Karen Briley-Saebo
  • Stephen Ward
  • Tiangui Huang
  • George Wang
  • Toshiyuki Takai
  • Clifford A Lowell
  • Savio L C Woo
  • Ying Chen
  • Deborah L French
  • Wen Chin Yang
  • Chun Yu Yen
  • Gordon Keller
  • Sofia Casares
  • Max Sung
  • Myron Schwartz
  • David E Levy
  • Jonathan Bromberg
  • Qingsheng Li
  • Alice I Sato

Detail Information

Publications12

  1. pmc Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy
    Samuel Eisenstein
    Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA
    Cancer Res 73:5003-15. 2013
    ..Our results offer a preclinical proof-of-concept for using MDSCs to facilitate and enhance the tumor-killing activity of tumor-targeted oncolytic therapeutics...
  2. doi The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies
    Junko Ozao-Choy
    Departments of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York, USA
    Cancer Res 69:2514-22. 2009
    ..These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies...
  3. ncbi Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells
    Zuping Zhou
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
    Stem Cells 28:620-32. 2010
    ..The successful in vitro generation of MDSCs may represent a critical step toward potential clinical application of MDSCs...
  4. pmc Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells
    Ge Ma
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, Room 13 02, New York, NY 10029 6574, USA
    Immunity 34:385-95. 2011
    ..Inhibition of the PIR-B signaling pathway promoted MDSC differentiation into M1 macrophages...
  5. pmc A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer
    Marcia Meseck
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Immunother 34:175-82. 2011
    ..Process development of this clinical agent has been discussed with the Food and Drug Administration in a pre-Investigational New Drug meeting and presented to the Office of Biotechnology Activities in a public hearing...
  6. doi Myeloid-derived suppressor cells prevent type 1 diabetes in murine models
    Bingjiao Yin
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Immunol 185:5828-34. 2010
    ....
  7. pmc Myeloid-derived suppressor cells: natural regulators for transplant tolerance
    Peter Boros
    Recanati Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY, USA
    Hum Immunol 71:1061-6. 2010
    ....
  8. pmc Targeting immune suppressing myeloid-derived suppressor cells in oncology
    Johnny Kao
    Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, United States
    Crit Rev Oncol Hematol 77:12-9. 2011
    ..Since c-kit can be readily inhibited by several small molecule inhibitors including imatinib, sunitinib and dasatinib, targeting immune suppressing cells can be readily accomplished in the clinic...
  9. pmc Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer
    Ping Ying Pan
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
    Cancer Res 70:99-108. 2010
    ..Blockade of CD40-CD40L interaction between MDSC and Treg may provide a new strategy to ablate tumoral immune suppression and thereby heighten responses to immunotherapy...
  10. pmc Advancements in immune tolerance
    Ping Ying Pan
    Department of Gene and Cell Medicine, Mount Sinai School od Medicine, New York, NY 10029, USA
    Adv Drug Deliv Rev 60:91-105. 2008
    ..This review briefly summarizes the major tolerogenic cell populations and their mechanisms of action, while focusing mainly on potential exploitation of their tolerogenic mechanisms for clinical applications...
  11. ncbi Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host
    Bo Huang
    Departments of Gene and Cell Medicine and General Surgery, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA
    Cancer Res 66:1123-31. 2006
    ..Our data provide evidence that Gr-1(+)CD115(+) MSC can mediate the development of Treg in tumor-bearing mice and show a novel immune suppressive mechanism by which MSCs can suppress antitumor responses...