Myeloid derived suppressor cells (MDSC) represent one of the most powerful mechanisms used by tumors to evade the immune response and create T cell tolerance. During the previous cycle of this grant, we studied murine and human MDSC. Our data demonstrated that MDSC expressing arginase I deplete L-arginine from the microenvironment, triggering activation of the GCN2 kinase pathway which eventually leads to an arrest in T cell cycle progression, inhibition of IFN? production, and blocking of signaling through the T cell receptor. Other researchers have recently described three additional mechanisms by which MDSC may suppress T cell function, namely the production of peroxynitrites, the production of H2O2, and the induction of regulatory T cells. Therefore, it is essential to identify the primary mechanism by which MDSC induce T cell tolerance in vivo so targeted therapies that block MDSC function can be designed and tested. To achieve this goal, we developed a new strain of conditional arginase I knock-out mice (full knock-outs die soon after birth) in which arginase I is deleted only in the CD11b+ myeloid cells. We have also established additional murine knock-out colonies to study and compare the proposed mechanisms for the induction of T cell tolerance by MDSC. Our preliminary data continue to support the hypothesis that MDSC expressing arginase I deplete L-Arginine in the tumor microenvironment and thereby cause T cell tolerance. Inhibiting arginase I will result in the development of a protective anti-tumor T cell response. In addition, our data shows that human tumors activate and promote the survival of MDSC, allowing them to accumulate in cancer patients. Inhibiting these tumor derived signals may also represent a new therapeutic approach to blocking MDSC. To definitively identify the mechanisms by which MDSC induce T cell tolerance and determine how human tumors activate MDSC, we propose the following Specific Aims. 1. Test the hypothesis that the primary mechanism for the induction of T cell tolerance by MDSC is the production of Arginase I. 2. Determine the mechanism(s) by which MDSC induce T cell tolerance in vivo and determine its effect on the anti-tumor response. 3. Determine the mechanisms by which tumors promote the survival and inhibit apoptosis of human MDSC. 4. Determine which is the predominant mechanism for the induction of T cell tolerance by human MDSC.

Public Health Relevance

Cancer cells are capable of turning specific subsets of white blood cells that are normally protective against infection into efficient inhibitors of the host's anti-cancer response. These cells, called myeloid derived suppressor cells (MDSC), block the ability of lymphocytes to kill tumor cells. By determining how tumors activate MDSC and how MDSC block the protective anti-cancer response, the proposed research will enable us to develop new treatments that block the suppressive activity of MDSC and release the protective anti- tumor immune response in patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA107974-07
Application #
8220727
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2004-04-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
7
Fiscal Year
2012
Total Cost
$294,654
Indirect Cost
$87,151
Name
Louisiana State Univ Hsc New Orleans
Department
Pediatrics
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Hossain, Fokhrul; Al-Khami, Amir A; Wyczechowska, Dorota et al. (2015) Inhibition of Fatty Acid Oxidation Modulates Immunosuppressive Functions of Myeloid-Derived Suppressor Cells and Enhances Cancer Therapies. Cancer Immunol Res 3:1236-47
Fletcher, Matthew; Ramirez, Maria E; Sierra, Rosa A et al. (2015) l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res 75:275-83
Dimitriades, Victoria; Rodriguez, Paulo C; Zabaleta, Jovanny et al. (2014) Arginase I levels are decreased in the plasma of pediatric patients with atopic dermatitis. Ann Allergy Asthma Immunol 113:271-5
Naura, Amarjit S; Kim, Hogyoung; Ju, Jihang et al. (2013) Minocycline blocks asthma-associated inflammation in part by interfering with the T cell receptor-nuclear factor ýýB-GATA-3-IL-4 axis without a prominent effect on poly(ADP-ribose) polymerase. J Biol Chem 288:1458-68
Guo, Gang; Marrero, Luis; Rodriguez, Paulo et al. (2013) Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res 73:1668-75
Hill, James M; Stern, Ethan M; Bhattacharjee, Partha S et al. (2013) The antimicrobial agent C31G is effective for therapy for HSV-1 ocular keratitis in the rabbit eye model. Antiviral Res 100:14-9
Srivastava, Ratika; Geng, Degui; Liu, Yingjia et al. (2012) Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. Cancer Res 72:6209-16
Raber, Patrick; Ochoa, Augusto C; Rodriguez, Paulo C (2012) Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 41:614-34
Wilk, Anna; Waligorska, Agnieszka; Waligorski, Piotr et al. (2012) Inhibition of ER* induces resistance to cisplatin by enhancing Rad51-mediated DNA repair in human medulloblastoma cell lines. PLoS One 7:e33867
Naura, Amarjit S; Zerfaoui, Mourad; Kim, Hogyoung et al. (2010) Requirement for inducible nitric oxide synthase in chronic allergen exposure-induced pulmonary fibrosis but not inflammation. J Immunol 185:3076-85

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