Conventional chemotherapy can effectively treat the symptom of cancer initially, but its efficacy is often compromised by late tumor relapse. Many chemotherapeutic agents are shown to have immunostimulatory effects, and these findings drive a growing interest in combining chemotherapy and immunotherapy for synergistic antitumor effects and improved clinical outcomes. The goal of this project is to understand how antitumor CD4 effector T cells can be utilized to activate host immunity and prevent tumor re-growth after chemotherapy. Our central hypothesis is that successful tumor eradication after chemotherapy is attainable only if highly activated polyfunctional CD4 effector T cells can be created and maintained. The significance of the study is that it identifies antitumor CD4 effector T cells as a key """"""""gatekeeper"""""""" of the overall host immunity, whose functional status (polyfunctional vs. tolerized) fundamentally drives the choice between eradication versus re-growth of residual tumors. The proposed project focuses on developing strategies to induce and maintain polyfunctional CD4 effector T cells in the post-chemotherapy immune milieu, and sustain the productive engagement of these cells with other immune cells to mount durable antitumor responses. We will attain these objectives by pursuing three highly-integrated specific aims.
In aim 1, we will elucidate how type I IFN activates antigen-presenting cells, and acts in concert with IL7 to confer polyfunctional effector properties to CD4 T cells in the post-chemotherapy window.
In aim 2, we will investigate the mechanisms of action of antitumor CD4 effector T cells in modifying the tumor milieu and driving effective CD8 responses. We will also elucidate the intrinsic (PD1) and extrinsic (Treg) inhibitory mechanisms that limit the durable effectiveness of CD4 effector T cells.
In aim 3, we will translate the mechanistic insights from aims 1 and 2 into a combinatorial therapeutic strategy that targets mutually-reinforcing immune pathways, including CD40 ligation, PD1 blockade and provision of exogenous IL7, all of which converge to achieve a durable polyfunctional CD4 response and lasting antitumor immunity. Successful completion of this project will provide mechanistic basis for the design and implementation of effective combination chemoimmunotherapies for various cancers.

Public Health Relevance

One of the most common problems in cancer patients who choose to undergo conventional chemotherapy is tumor recurrence. This project will elucidate the critical role of CD4 effector T cells in controlling host antitumor immunity after chemotherapy. This may lead to the development of curative chemoimmunotherapy strategies that capitalize on the potential of tumor-reactive CD4 T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA158202-01A1
Application #
8238574
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$280,125
Indirect Cost
$93,375
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Ding, Zhi-Chun; Liu, Chufeng; Cao, Yang et al. (2016) IL-7 signaling imparts polyfunctionality and stemness potential to CD4(+) T cells. Oncoimmunology 5:e1171445
Paschall, Amy V; Zhang, Ruihua; Qi, Chen-Feng et al. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol 194:2369-79
Wei, Jin-xing; Lv, Li-hong; Wan, Yun-le et al. (2015) Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology 61:1284-94
Luo, Liqun; Zhu, Gefeng; Xu, Haiying et al. (2015) B7-H3 Promotes Pathogenesis of Autoimmune Disease and Inflammation by Regulating the Activity of Different T Cell Subsets. PLoS One 10:e0130126
Lu, Xiaoyun; Ding, Zhi-Chun; Cao, Yang et al. (2015) Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. J Immunol 194:2011-21
Cui, Hongmei; Guo, Mingxiong; Xu, Dong et al. (2015) The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun 6:6752
Xu, Yiming; An, Xiaofei; Guo, Xin et al. (2014) Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol 34:1231-9
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53
Marabelle, Aurélien; Kohrt, Holbrook; Sagiv-Barfi, Idit et al. (2013) Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123:2447-63
Ding, Zhi-Chun; Huang, Lei; Blazar, Bruce R et al. (2012) Polyfunctional CD4⁺ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood 120:2229-39

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