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 #
5R01CA184185-04
Application #
9208127
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
4
Fiscal Year
2017
Total Cost
$305,261
Indirect Cost
$99,386
Name
Augusta University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Mohamed, Eslam; Al-Khami, Amir A; Rodriguez, Paulo C (2018) The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates. Cell Mol Immunol 15:421-427
Hossain, Fokhrul; Majumder, Samarpan; Ucar, Deniz A et al. (2018) Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses. Front Immunol 9:1288
Sharma, Madhav D; Rodriguez, Paulo C; Koehn, Brent H et al. (2018) Activation of p53 in Immature Myeloid Precursor Cells Controls Differentiation into Ly6c+CD103+ Monocytic Antigen-Presenting Cells in Tumors. Immunity 48:91-106.e6
Song, Minkyung; Sandoval, Tito A; Chae, Chang-Suk et al. (2018) IRE1?-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562:423-428
Fouda, Abdelrahman Y; Xu, Zhimin; Shosha, Esraa et al. (2018) Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. Cell Death Dis 9:1001
Caldwell, R William; Rodriguez, Paulo C; Toque, Haroldo A et al. (2018) Arginase: A Multifaceted Enzyme Important in Health and Disease. Physiol Rev 98:641-665
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
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
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
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

Showing the most recent 10 out of 27 publications