Myeloid-Derived Suppressor Cells (MDSC) expressing Arginase (ARG) 1 are potent inhibitors of T cell function in cancer. MDSC deplete L-Arginine (L-Arg) in serum and the tumor microenvironment, severely impairing anti- tumor responses. Work done in the preceding five years identified the mechanisms by which MDSC deplete L- Arg and has started to identify the molecular mechanisms by which L-Arg depletion causes T cell anergy. We found that MDSC expressing ARG 1 infiltrate tumors and deplete L-Arg by rapid incorporation through CAT transporters. This L-Arg-depleted environment causes a T cell cycle arrest by inhibiting cyclin D3 and cdk4 (but not cyclin D2 or cdk6), inhibits the production of IFNg (but not IL2), and blocks the expression of the T cell receptor z chain (CD3z), severely impairing T cell function. Inhibition of ARG 1 re-establishes proliferation, IFNg production, and CD3z expression, and triggers an anti-tumor response. These mechanisms were found in mice and patients with cancer. Our results therefore suggest that L-Arg depletion triggers the selective inhibition of specific genes important for effector functions of T cells, and not a generalized decrease in protein synthesis from nutrient starvation. The data also suggest that this phenomenon is caused by the activation of a checkpoint that mediates the inhibition of these effector mechanisms. Therefore, blocking this checkpoint may make T cells resistant to the anergizing/tolerizing effect of MDSC. The proposed research will identify the molecular mechanisms triggered by L-Arg depletion that inhibit the expression of genes and proteins necessary for T cell effector functions. We will demonstrate the importance of these mechanisms in tumor- bearing mice and cancer patients, and will design and test novel therapeutic approaches that combine the inhibition of MDSC with the protection of T cells from the tolerizing tumor microenvironment.

Public Health Relevance

This proposed research will determine how Myeloid-Derived Suppressor Cells (MDSC) inhibit T cells and will test new therapies designed to enhance the potential of immunotherapy for cancer patients. Cancer vaccines and cytokines can be an important therapeutic approach for patients whose tumors have failed standard forms of treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-ONC-S (02))
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Louisiana State Univ Hsc New Orleans
Schools of Medicine
New Orleans
United States
Zip Code
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
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
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
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
Highfill, Steven L; Rodriguez, Paulo C; Zhou, Qing et al. (2010) Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 116:5738-47
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
Hernandez, Claudia P; Morrow, Kevin; Lopez-Barcons, Lluis A et al. (2010) Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood 115:5214-21
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

Showing the most recent 10 out of 21 publications