Metabolic Control of DC Fate and Function for Breast Cancer Immunotherapy
Abstract
Breast cancer is still the second leading cause of cancer-related death in women in the United States and throughout the world. Immunotherapy is a promising approach for treating patients with advanced breast cancer. However, immunosuppressive microenvironments induced by regulatory T cells (Treg) present a major barrier to successful anti-tumor immunotherapy. Defining the suppressive mechanisms used by different types of tumor-infiltrating Treg cells is essential for the development of novel strategies to treat human breast cancer. We recently discovered high percentages of gamma delta Treg cells existing among the tumor-infiltrating lymphocytes (TILs) of breast tumor patients, which are strongly negatively correlated with clinical outcomes. We further identified a novel suppressive mechanism whereby gamma delta Treg cells induce senescence in T cells and dendritic cells (DCs) that then also develop potent suppressive activity. Therefore, it is critical to further identify the molecular mechanisms responsible for gamma delta Treg-induced senescence and suppressive effects and to develop strategies to reverse senescence induction mediated by gamma delta Treg cells. Increasing evidence indicates that the ability of a lymphocyte to perform functional immune responses is controlled by pathways of energy metabolism. However, little is known about the regulation of energy metabolism in tolerogenic DCs in the tumor suppressive microenvironment. We recently found that gamma delta Treg cells dramatically inhibit DC lipid metabolism, including cholesterol synthesis, fatty acid oxidation and synthesis. Importantly, these senescent DCs also develop strong suppressive activity and inhibit the subsequent adaptive anti-tumor immunity. The central hypotheses of this proposal are that: (1) breast cancer-derived gamma delta Treg cells can rewrite lipid metabolism in DCs, resulting in DC senescence with tolerogenic phenotypes and functions; and (2) blockage of senescence in DCs induced by Treg cells is a critical checkpoint to control Treg suppression, which will provide a novel target for cancer immunotherapy. Specific Aim 1 seeks to identify what lipid species are lacking in gamma delta Treg-induced senescent DCs and whether the altered lipid components are causatively related to the DC senescence and impaired functions. Specific Aim 2 will then investigate the importance of transcription factors STAT1/STAT3 and PD1-PDL1 signaling in controlling lipid metabolism imbalance, senescence induction, and impaired functions detected in gamma delta Treg-treated DCs. Specific Aim 3 will investigate whether checkpoint blockade of PD-L1 combined with STAT1/3 signaling inhibition in DCs can serve as novel strategies to reprogram DC metabolism and synergistically enhance anti-tumor immunity for breast cancer immunotherapy. These studies should not only improve our mechanistic understanding of the precise metabolic processes of tolerogenic DCs suppressed by Treg cells in the tumor microenvironment, but also lead to novel strategies to reprogram innate immune cell metabolism for future breast cancer immunotherapy. Career goals in breast cancer: My goal is to understand how breast cancer cells escape the immune surveillance and to develop effective immunotherapeutic strategies against human breast cancers. By the completion of this proposed project, I will have a thorough understanding of novel and established immunological techniques as well as a background in immunotherapy of breast cancer. Receipt of this award will also allow me to become an independent investigator in the field of breast cancer immunology and immunotherapy. The outcomes of the proposed studies: The proposed studies in this application will augment fundamental understanding of the suppressive mechanisms induced by breast cancer cells in the tumor microenvironment. Furthermore, these studies should lead to novel strategies for manipulation of the breast cancer-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010006
Entities
People
- Xia Liu
Organizations
- Saint Louis University
- United States Army