Date of Award

2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

M. Rita I. Young

Second Advisor

Amanda C. LaRue

Third Advisor

Shikhar Mehrotra

Fourth Advisor

Christopher Parsons

Fifth Advisor

Steven A. Rosenzweig

Abstract

While studies have indicated that squamous cell carcinoma of the head and neck (HNSCC) is associated with immune suppression, these studies did not analyze the immune response at the dysplastic stage. This study utilized a mouse model of 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis to examine the alterations in immune phenotype at the premalignant and malignant stages of HNSCC. Cervical lymph nodes of HNSCC-bearing mice were found to contain a greater number of cells, including a greater number of conventional (Tconv) and regulatory (Treg) T cells, compared to lymph nodes of control and premalignant lesion-bearing mice. Premalignant lesion-bearing mouse lymph nodes consist of a greater percentage of Tconv cells expressing markers for activation, memory, and exhaustion compared to both control and HNSCC-bearing mice. Lymph nodes from both premalignant lesion-bearing and HNSCC-bearing mice include increased numbers of Th1, Tc1 and Th17 cells compared to control mice. The data show that while there is the expected increase in Tregs in lymph nodes when HNSCC is present, there is also an unexpected increase in immune populations usually associated with a beneficial anti-tumor response. In addition, the results demonstrate that the premalignant stage of HNSCC development is associated with a robust immune response involving an increase in inflammatory cells. The use of dendritic cell (DC) vaccines as treatment for malignancy is complicated by the immune evasion tactics often employed by carcinomas such as HNSCC. This study aims to determine if an immune response can be elicited by administering a DC vaccine during the premalignant stages of HNSCC, prior to development of immune escape. Bone marrow-derived DCs were pulsed with premalignant lesion lysate (DCpm) and administered to 4NQO-treated mice exhibiting premalignant lesions. Endoscopic examination revealed that DCpm vaccination and control vaccination with dendritic cells pulsed with normal tongue epithelium lysate (DCnt) significantly decreased lesion burden. Analysis of lymph node cells revealed that while DCnt vaccination resulted in a rapid increase in total lymphocyte count, levels of activated Tconv cells, and Th1, Tel, Th17, Te17, and Th2 cells, DCpm vaccination results in a delayed, yet substantial, increase in these immune effector mechanisms. This suggests that dendritic cell vaccination may have a beneficial effect on clinical outcome regardless of type of antigenic stimulation, and DCs pulsed with premalignant lysate rather than normal tongue epithelium lysate result in a delayed immune effector response upon vaccination of premalignant lesion-bearing mice.

Rights

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