Chronic inflammation may contribute to tumor initiation, progression and metastasis. However, the precise mechanism remains to be fully understood. Recent studies indicate that an integral element of tumor biology is the immunologic effects of oncogenic changes, and the quality and state of local inflammation and immune responses are crucial factors controlling carcinogenesis and cancer progression. Mechanisms of immune interactions within the tumor microenvironment are a critical and understudied area of cancer immunology that will impact significantly on the success of immunotherapeutic strategies. IL-17+CD4+ T (Th17) and IL-22+CD4+ T (Th22) cells are found in oropharyngeal cancer. The nature of Th17 and Th22 cells is poorly understood in human oropharyngeal cancer. Our preliminary studies have demonstrated that Th17 and Th22 subsets may be functionally and mechanistically different in the context of oropharygeal cancer. Based on our preliminary data, our specific aims are:
Aim 1 : To test our hypothesis that Th17 cells have stem cell feature in oropharyngeal cancer Aim 2: To test our hypothesis that Th17 cells epigenetically impact oropharyngeal cancer immunity Aim 3: To test our hypothesis that Th22 cells promote cancer stemness, and Th17/Th22 cells affect patient outcome in oropharyngeal cancer.

Public Health Relevance

Our understanding of T cell subsets in the human tumor microenvironment lags much behind the more comprehensive analyses of these cells in mouse autoimmune disease models. This deficiency significantly tempers our efforts toward understanding basic human T cell biology and the potential interaction between Th cell subsets and cancer cells including cancer stem cells. The application takes a comprehensive approach by combining basic immunological methods, genetic research, and clinical and comparative analyses to address the nature of immune regulation in the microenvironment of oropharyngeal cancer. The application is conceptually and applicably significant, and will generate novel insight into new approaches in cancer immune therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA171306-01A1
Application #
8577165
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2013-07-01
Project End
2018-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$534,676
Indirect Cost
$190,833
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Crespo, Joel; Wu, Ke; Li, Wei et al. (2018) Human Naive T Cells Express Functional CXCL8 and Promote Tumorigenesis. J Immunol 201:814-820
Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572
Crespo, Joel; Vatan, Linda; Maj, Tomasz et al. (2017) Phenotype and tissue distribution of CD28H+ immune cell subsets. Oncoimmunology 6:e1362529
Maj, Tomasz; Wang, Wei; Crespo, Joel et al. (2017) Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18:1332-1341
Zhao, Ende; Maj, Tomasz; Kryczek, Ilona et al. (2016) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 17:95-103
Sun, Danfeng; Lin, Yanwei; Hong, Jie et al. (2016) Th22 cells control colon tumorigenesis through STAT3 and Polycomb Repression complex 2 signaling. Oncoimmunology 5:e1082704
Peng, Dongjun; Tanikawa, Takashi; Li, Wei et al. (2016) Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling. Cancer Res 76:3156-65
Nagarsheth, Nisha; Peng, Dongjun; Kryczek, Ilona et al. (2016) PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 76:275-82
Zou, Weiping; Wolchok, Jedd D; Chen, Lieping (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 8:328rv4
Hoesli, Rebecca C; Moyer, Jeffrey S (2016) Immunotherapy for Head and Neck Squamous Cell Carcinoma. Curr Oral Health Rep 3:74-81

Showing the most recent 10 out of 17 publications