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. A better understanding of the suppressive mechanisms utilized by different types of tumor-infiltrating Treg cells is essential for the development of novel strategies to trea human cancers. Conventional Treg cells have been extensively studied, however, little is known about the negative regulation mediated by ?? T cells in anti-tumor immune responses in cancer patients. We recently discovered high percentages of ?? 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 ?? 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 ?? Treg-induced senescence and suppressive effects, and to develop strategies to reverse senescence induction mediated by ?? Treg cells. Our long-term goals are to identify the immunoregulatory mechanisms utilized by tumor-associated Treg cells and develop strategies to modify their suppressive effects for improved cancer treatment. The central hypotheses of this proposal are that: 1) breast tumor-derived ?? Treg cells not only can directly suppress na?ve/effector T cells and DCs, but also can direct their differentiation into senescent cells with altered biological functions that amplify immune suppression; 2) immune suppression and senescence induction mediated by ?? Treg cells can be blocked by TLR8 signaling, thereby resulting in enhanced anti-tumor immunity.
Specific Aim 1 seeks to determine the molecular and biological alterations induced by human breast tumor-derived ?? Treg cells in nave /effector T cells leading to T cell senescence. We will then identify the importance of ERK1/2 and p38 signaling in controlling senescence induction in ?? Treg-treated responder T cells.
Aim 2 will investigate the amplified immune suppression in adaptive immunity mediated by ?? Treg-induced senescent DCs and further identify the mechanisms responsible for the tolerogenic functions of senescent DCs. We will then perform in vivo studies to investigate how ?? Treg- induced senescent DCs affect tumor-specific effective immune responses in breast cancer models.
Aim 3 will first dissect the mechanisms responsible for TLR8 signaling-mediated reversal of ?? Treg suppression and senescence induction in responder T cells involving glucose metabolism changes in ?? Treg cells. We will then investigate the enhancement of anti-tumor immunity through manipulation of TLR8 signaling and/or glucose metabolism in ?? Treg cells preventing generation of senescent tumor-specific T cells in vivo in breast cancer immunotherapy models. A positive outcome from these studies should lead to novel strategies for manipulation of ?? Treg-induced suppression for the treatment of human breast cancer and other cancers as well.

Public Health Relevance

The proposed studies address the important areas of breast cancer that is the second leading cause of cancer-related death in women throughout the world, and the regulatory T cell-induced tumor immunosuppressive microenvironment that is a major barrier for successful anti-tumor immunotherapy. The proposed research has relevance to public health, because it seeks to dissect novel suppressive mechanisms and then to develop strategies that control immune suppression mediated by ?? regulatory T cells in human breast cancer. Thus, the findings are ultimately expected to improve treatment of human breast cancer and other cancers as well.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA184379-05
Application #
9657658
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Kuo, Lillian S
Project Start
2015-03-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2021-02-28
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Li, Lingyun; Liu, Xia; Sanders, Katherine L et al. (2018) TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metab :
Huang, Lan; Xu, Huaxi; Peng, Guangyong (2018) TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy. Cell Mol Immunol 15:428-437
Liu, Xia; Mo, Wei; Ye, Jian et al. (2018) Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun 9:249
Lin, Jianguo; Haridas, Seema; Barenkamp, Stephen J et al. (2018) Neonatal neutrophils stimulated by group B Streptococcus induce a proinflammatory T-helper cell bias. Pediatr Res 83:739-746
Ye, Jian; Wang, Yadan; Liu, Xia et al. (2017) TLR7 Signaling Regulates Th17 Cells and Autoimmunity: Novel Potential for Autoimmune Therapy. J Immunol 199:941-954
Ye, Jian; Peng, Guangyong (2015) Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy. Oncoimmunology 4:e994398
Huang, Yi; Ma, Chunling; Zhang, Qunyuan et al. (2015) CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome. Oncotarget 6:17462-78
Ye, Jian; Ma, Chunling; Hsueh, Eddy C et al. (2014) TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol Med 6:1294-311