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 TCRáâ-/- 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 (TCRáâ+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 IFNã, TNFá 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 IFNã and TNFá. To our knowledge, this is the first demonstration of increased carcinogenesis attributable to CD8+ TILs, characterized by their high IFNã, TNFá, 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.
| Identifer | oai:union.ndltd.org:YALE_med/oai:ymtdl.med.yale.edu:etd-08232007-122524 |
| Date | 09 April 2008 |
| Creators | Ng, Bernice Yu Jing |
| Contributors | Michael Girardi, MD |
| Publisher | Yale University |
| Source Sets | Yale Medical student MD Thesis |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://ymtdl.med.yale.edu/theses/available/etd-08232007-122524/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Yale School of Medicine or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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