Patients with select premalignant oral lesions have a high risk of secondary lesions and oral squamous cell carcinoma (OSCC). Immune therapies hold promise for OSCC, but are discouraged by the immune suppression they induce. An alternative is immune treatment of patients with high risk premalignant lesions. We hypothesize that oral premalignant lesions can be used in dendritic cell vaccines to stimulate protective immunity targeting shared tumor antigens on premalignant lesions and OSCC. The rationale for this hypothesis is based on our studies showing that dysplastic premalignant lesions share overexpression of tumor antigens with OSCC. The most prominent shared antigens are epidermal growth factor receptor (EGFR), the receptor for advanced glycation end products (RAGE) and the MUC1 mucin.
The specific aims that will test our hypothesis are: 1. To stimulate patient T-cell reactivity in vitro to premalignant lesions and OSCC using dendritic cells pulsed with autologous premalignant lesion cells and to determine if reactivity targets EGFR, RAGE and/or MUC1. a. To use premalignant lesion-pulsed dendritic cells in vitro to stimulate autologous T-cell reactivity to premalignant lesions and OSCC. b. To determine the extent to which the immune reactivity that is generated in response to premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. 2. To skew the immune phenotype within premalignant oral lesions into protective immune reactivity against premalignant oral lesions and OSCC in a carcinogen-induced premalignant lesion mouse model. a. To determine if vaccination using dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells skews the local immune phenotype into reactivity against premalignant lesions and OSCC. b. To determine in vivo if vaccination with dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells stimulates protective immunity against premalignant oral lesions and OSCC. c. To determine the extent to which the protective immune reactivity that is generated in response to vaccination with premalignant lesion-pulsed dendritic cells is targeted at EGFR, RAGE and MUC1. d. To determine if vaccination with dendritic cells pulsed with peptides derived from EGFR, RAGE and MUC1 will confer protective immune reactivity to premalignant lesions and their progression to OSCC. These studies are expected to show that vaccination against premalignant oral lesions stimulates immunity against premalignant lesions and OSCC. Identifying the target antigens against which protective immunity is elicited allow use of peptides from these antigens in vaccines for patients at high risk for lesions and OSCC.

Public Health Relevance

Oral squamous cell carcinoma is the 6th most common neoplasm in the world with a 5 year survival of less than 50%. The proposed studies have direct relevance to the goal of reducing oral cancer development from premalignant oral lesions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA128837-05
Application #
8403804
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2009-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$238,391
Indirect Cost
$49,192
Name
Medical University of South Carolina
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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 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
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 1α,25-Dihydroxyvitamin D3 Treatment upon Cancer Diagnosis. Cancers (Basel) 7:1109-24
Woodford, Danielle; Johnson, Sara D; De Costa, Anna-Maria A et al. (2014) An Inflammatory Cytokine Milieu is Prominent in Premalignant Oral Lesions, but Subsides when Lesions Progress to Squamous Cell Carcinoma. J Clin Cell Immunol 5:
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
Vielma, Silvana A; Klein, Richard L; Levingston, Corinne A et al. (2014) Skewing of immune cell cytokine production by mediators from adipocytes and endothelial cells. Adipocyte 3:126-31
Vielma, Silvana A; Klein, Richard L; Levingston, Corinne A et al. (2013) Adipocytes as immune regulatory cells. Int Immunopharmacol 16:224-31
Young, M Rita I; Day, Terry A (2013) Immune regulatory activity of vitamin d3 in head and neck cancer. Cancers (Basel) 5:1072-85
Vielma, Silvana A; Klein, Richard L; Levingston, Corinne A et al. (2013) Premalignant lesions skew spleen cell responses to immune modulation by adipocytes. Anticancer Res 33:1809-18
Walker, David D; Reeves, Travis D; de Costa, Anna-Maria et al. (2012) Immunological modulation by 1α,25-dihydroxyvitamin D3 in patients with squamous cell carcinoma of the head and neck. Cytokine 58:448-54

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