Accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts is an important mechanism of suppression of T and NK cell responses and a major obstacle to immunotherapy. MDSC inhibitory activity has been attributed to several pathways, including the depletion of the amino acids arginine and cysteine; the release of reactive oxygen species, peroxynitrites, and prostaglandin E2; and the induction of regulatory T cells. Unfortunately, the understanding of the immune-inhibitory mechanisms induced by MDSC has not yet been translated into successful therapies to globally block MDSC function in cancer. We postulate that the identification and inhibition of the central mediators of MDSC-immune regulatory activity in tumors will overcome T cell suppression and increase the efficacy of T cell-based immunotherapies. In this proposal, we aim to determine the role of the C/EBP homologous stress-related protein (Chop), a common stress sensor usually associated with the induction of cellular apoptosis, as a master regulator of the immune suppressive activity of MDSC. We hypothesize that the induction of Chop in MDSC by multiple stress-related factors, globally drives the ability of MDSC to inhibit T cell responses and modulates MDSC turnover/survival homeostasis. Therefore, therapeutic inhibition of Chop or its upstream mediators in tumors will block MDSC function, restore protective anti-tumor effector T cell responses, and increase the efficacy of T cell-based immunotherapies. This hypothesis is based upon our extensive preliminary findings suggesting the central role of Chop on MDSC activity. We will test our hypothesis and achieve the objectives of this study through the following Specific Aims: (1) To determine the mechanisms by which the expression of Chop in the stroma regulates the immune suppression activity and the accumulation of MDSC in tumors. (2) To determine the mechanisms that induce Chop expression in tumor-infiltrating MDSC. (3) To test the prediction that pharmacological inhibition or genetic deletion of Chop will block MDSC function and increase the efficacy of T cell-based immunotherapies in cancer. Completion of the proposed study will describe for the first time how multiple stress factors in tumors drive global MDSC activity through a unique pathway. In addition, the results will help characterize and develop a novel therapeutic approach, which carries the potential to block the global immune inhibitory functions of MDSC and to restore protective T cell immunity in cancer. Moreover, the methodology established in this proposal could be applied into other diseases where MDSC are major mediators of T cell suppression.

Public Health Relevance

Inhibition of immune responses in tumor-bearing hosts represents a major limitation for the development of successful immune-based therapies in cancer. This proposal will identify the role of C/EBP homologous stress- related protein (Chop) as a master regulator of myeloid-derived suppressive cells (MDSC) function, and will test the therapeutic inhibition of Chop, and its upstream mediators, as approaches to increase the efficacy of T cell-based immunotherapy in cancer. Information garnered from this effort is expected to provide insights into the mechanisms underlying the accumulation and immune suppressive activity of MDSC in cancer, which may enable the design of new therapeutic approaches to prevent and/or reverse immune dysfunction in tumor- bearing hosts.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA184185-01A1
Application #
8817975
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2015-03-01
Project End
2015-08-14
Budget Start
2015-03-01
Budget End
2015-08-14
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Cubillos-Ruiz, Juan R; Mohamed, Eslam; Rodriguez, Paulo C (2017) Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. J Immunother Cancer 5:5
Al-Khami, Amir A; Rodriguez, Paulo C; Ochoa, Augusto C (2017) Energy metabolic pathways control the fate and function of myeloid immune cells. J Leukoc Biol 102:369-380
Achyut, B R; Angara, Kartik; Jain, Meenu et al. (2017) Canonical NF?B signaling in myeloid cells is required for the glioblastoma growth. Sci Rep 7:13754
Al-Khami, A A; Ghonim, M A; Del Valle, L et al. (2017) Fuelling the mechanisms of asthma: Increased fatty acid oxidation in inflammatory immune cells may represent a novel therapeutic target. Clin Exp Allergy 47:1170-1184
Rodriguez, Paulo C; Ochoa, Augusto C; Al-Khami, Amir A (2017) Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity. Front Immunol 8:93
Dai, Lu; Bai, Aiping; Smith, Charles D et al. (2017) ABC294640, A Novel Sphingosine Kinase 2 Inhibitor, Induces Oncogenic Virus-Infected Cell Autophagic Death and Represses Tumor Growth. Mol Cancer Ther 16:2724-2734
Munn, David H; Sharma, Madhav D; Johnson, Theodore S et al. (2017) IDO, PTEN-expressing Tregs and control of antigen-presentation in the murine tumor microenvironment. Cancer Immunol Immunother 66:1049-1058
Mohamed, Eslam; Cao, Yu; Rodriguez, Paulo C (2017) Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol Immunother 66:1069-1078
Islam, Bianca N; Sharman, Sarah K; Hou, Yali et al. (2017) Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice. Cancer Prev Res (Phila) 10:377-388
Sultan, Hussein; Trillo-Tinoco, Jimena; Rodriguez, Paulo et al. (2017) Effective antitumor peptide vaccines can induce severe autoimmune pathology. Oncotarget 8:70317-70331

Showing the most recent 10 out of 21 publications