Premalignant oral lesions have increased levels of Th17 cells, which are replaced with Treg as lesions become head and neck squamous cell carcinomas (HNSCC). This study aims to prevent progression of premalignant lesions to HNSCC by capitalizing on the anti-tumor effects of Th17 cells. The hypothesis of this study is that sustained stimulation of reactivity mediated b IFN-?-expressing Th17 cells in premalignant oral lesions can promote immunological defenses against premalignant lesions and, consequently, prevent HNSCC. The premise of this hypothesis is that Th17 cells can be potent producers of IFN-?, exhibit antigen-specific activity, and recruit dendritic cells and Th1 T-cells. Also, our studies have shown (i) levels of IFN-?-expressing Th17 cells are increased in premalignant lesions, but are replaced with Treg during progression toward HNSCC, (ii) media conditioned by HNSCC skews the Th17 phenotype of cells from mice with premalignant lesions to a Treg phenotype, but IL-23 lessens the loss of Th17 cells, while neutralization of TGF? prevents development of Treg, (iii) inhibition of inflammation exacerbates lesion development. Our hypothesis will be tested in a carcinogen-induced mouse model in which premalignant oral lesions progress into HNSCC. In addition, studies will transition to assessing reactivity of Th17 cells from patients having premalignant oral lesions against autologous lesions. The following aims will test if sustaining the Th17 phenotype can result in protective immune activity against progression of premalignant lesions to HNSCC: 1. To sustain the Th17- IFN-? + cell phenotype as premalignant oral lesions progress toward HNSCC so as to stimulate lesion-specific immune reactivity and reduce progression to malignancy. a. Determine if sustaining the Th17 phenotype by stabilizing Th17 cells with IL-23 and/or preventing skewing toward Treg cells with a TGF-? receptor inhibitor sustains levels of IFN-? -producing Th17 cells with specificity toward premalignant lesions and HNSCC. b. Determine if stabilizing the Th17- IFN-? + phenotype stimulates immune infiltration that is reactive toward premalignant lesions and against the development of HNSCC. 2. To determine the extent to which Th17 cells from patients bearing premalignant oral lesions exhibit specificity toward autologous lesions and whether this activity can be further stimulated with peptides derived from tumor antigens that are prominently expressed on premalignant lesions and HNSCC. The proposed studies are expected to show that the Th17+ IFN-? + phenotype can promote protective immunity against premalignant oral lesions. Since a high proportion of premalignant oral lesions progress to HNSCC, protective immunity against lesions is expected to translate into reduced development of HNSCC.

Public Health Relevance

Oral cancer has received considerable attention in the VA due to its strong link with smoking plus alcohol, and the high incidence of these risk factors among the military and Veterans. Adding to this concern is the possible health impact of combustible product exposures during the Gulf War and exposure to burn pits and carcinogens in Iraq and Afghanistan. The proposed studies will test a novel strategy to prevent development of oral cancer by immunologically targeting premalignant oral lesions that have a high risk of developing into cancer. These studies will be applicable to other types of malignancies, including lung and prostate cancer, which are increasing in prevalence in the aging Veteran population. Thus, the studies being proposed are relevant to the aging VA population as well as the younger at-risk population of Veterans.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology A (ONCA)
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Ralph H Johnson VA Medical Center
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Young, M Rita I; Xiong, Ying (2018) Influence of vitamin D on cancer risk and treatment: Why the variability? Trends Cancer Res 13:43-53
Young, M Rita I (2017) Redirecting the focus of cancer immunotherapy to premalignant conditions. Cancer Lett 391:83-88
Levingston, Corinne A; Young, M Rita I (2017) Local Immune Responsiveness of Mice Bearing Premalignant Oral Lesions to PD-1 Antibody Treatment. Cancers (Basel) 9:
Young, M Rita I (2016) Th17 Cells in Protection from Tumor or Promotion of Tumor Progression. J Clin Cell Immunol 7:431
Wang, Zhewu; Mandel, Howard; Levingston, Corinne A et al. (2016) An exploratory approach demonstrating immune skewing and a loss of coordination among cytokines in plasma and saliva of Veterans with combat-related PTSD. Hum Immunol 77:652-657
Gattoni-Celli, Sebastiano; Young, M Rita I (2016) Restoration of Immune Responsiveness to Glioma by Vaccination of Mice with Established Brain Gliomas with a Semi-Allogeneic Vaccine. Int J Mol Sci 17:
Young, M Rita I; Levingston, Corinne A; Johnson, Sara D (2016) Treatment to sustain a Th17-type phenotype to prevent skewing toward Treg and to limit premalignant lesion progression to cancer. Int J Cancer 138:2487-98
Johnson, Sara D; Levingston, Corinne; Young, M Rita I (2016) Premalignant Oral Lesion Cells Elicit Increased Cytokine Production and Activation of T-cells. Anticancer Res 36:3261-70
Young, M Rita I; Levingston, Corinne; Johnson, Sara D (2015) Cytokine and Adipokine Levels in Patients with Premalignant Oral Lesions or in Patients with Oral Cancer Who Did or Did Not Receive 1?,25-Dihydroxyvitamin D3 Treatment upon Cancer Diagnosis. Cancers (Basel) 7:1109-24
Johnson, Sara D; De Costa, Anna-Maria A; Young, M Rita I (2014) Effect of the premalignant and tumor microenvironment on immune cell cytokine production in head and neck cancer. Cancers (Basel) 6:756-70

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