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.
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.
|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|
|Crittenden, Marka R; Savage, Talicia; Cottam, Benjamin et al. (2014) Expression of arginase I in myeloid cells limits control of residual disease after radiation therapy of tumors in mice. Radiat Res 182:182-90|
|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|
|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|
|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|
|Rodriguez, Paulo C; Hernandez, Claudia P; Morrow, Kevin et al. (2010) L-arginine deprivation regulates cyclin D3 mRNA stability in human T cells by controlling HuR expression. J Immunol 185:5198-204|
|Rodriguez, Paulo C; Ernstoff, Marc S; Hernandez, Claudia et al. (2009) Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 69:1553-60|
|Zabaleta, Jovanny; Su, L Joseph; Lin, Hui-Yi et al. (2009) Cytokine genetic polymorphisms and prostate cancer aggressiveness. Carcinogenesis 30:1358-62|
|Rodriguez, Paulo C; Ochoa, Augusto C (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunol Rev 222:180-91|
|Zabaleta, Jovanny; Lin, Hui-Yi; Sierra, Rosa A et al. (2008) Interactions of cytokine gene polymorphisms in prostate cancer risk. Carcinogenesis 29:573-8|
Showing the most recent 10 out of 14 publications