Date of Award

4-9-2008

Document Type

Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Michael Girardi, MD

Abstract

Chronic inflammation is associated with carcinoma development in several clinical settings, and we sought to investigate the role of T cells in this phenomenon using the DMBA/TPA two-stage chemical carcinogenesis protocol. We demonstrate that, paradoxical to models of immunosurveillance, wild-type (WT) mice have a markedly higher rate of tumor formation relative to strains lacking CD8+ T cells. Adoptive transfers of antibody-coated magnetic bead-enriched peripheral CD8+ T cells into TCRαβ-/- mice confirmed that the increased mean tumor area and progression to carcinoma was attributable to the presence of CD8+ T cells. All analyzed strains of mice in which the CD8 compartment was intact (WT, CD4-/-) showed significant increases in tumor susceptibility. Putative tumor-promoting (T-pro) cells (TCRαβ+CD8+CD44+CD62L- tumor infiltrating lymphocytes, TILs) were directly compared to their phenotypic equivalents in peripheral blood lymphocytes (PBLs). In WT and CD4-deficient mice, CD8+ TILs consistently revealed a markedly higher relative expression, by RT-PCR, of IFNγ, TNFα and COX-2, and a striking decrease in expression of perforin. Cytokine-bead analysis (CBA) comparison of CD8+ and CD4+ TIL in tumors from WT mice confirmed the increased expression by the CD8+ TIL of IFNγ and TNFα. To our knowledge, this is the first demonstration of increased carcinogenesis attributable to CD8+ TILs, characterized by their high IFNγ, TNFα, and COX-2 production and defective perforin production relative to phenotypically equivalent PBLs. These studies may have mechanistic implications for the role of T cells in inflammation-associated carcinogenesis.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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