Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis

Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6770-5. doi: 10.1073/pnas.0604982104. Epub 2007 Apr 5.

Abstract

There is a longstanding but poorly understood epidemiologic link between inflammation and cancer. Consistent with this, we previously showed that alphabeta T cell deficiency can increase resistance to chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate. This provoked the hypothesis that alphabeta T cell deficiency removed T regulatory cells that limit the anti-tumor response or removed a specific tumor-promoting (T-pro) T cell population. Here we provide evidence for the latter, identifying a novel CD8(+) subset that is a candidate for T-pro cells. We demonstrate that CD8 cell-deficient mice show substantially less tumor incidence and progression to carcinoma, whereas susceptibility is restored by CD8(+) cell reconstitution. To characterize the putative T-pro cells, tumor-infiltrating lymphocytes were isolated from normal and CD4(-/-) mice, revealing an activated population of T cell receptor alphabeta(+)CD8(+)CD44(+)CD62L(-) cells expressing the inflammatory mediators IFNgamma, TNFalpha, and cyclooxygenase-2, but deficient in perforin, relative to recirculating cells of equivalent phenotype. This novel population of CD8(+) T cells has intriguing similarities with other lymphocytes that have been associated with tissue growth and invasiveness and has implications for inflammation-associated carcinogenesis, models of cancer immunosurveillance, and immunotherapeutic strategies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology*
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / metabolism
  • Immunologic Deficiency Syndromes / pathology
  • Immunophenotyping
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • Receptors, Antigen, T-Cell, alpha-beta / deficiency
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Skin Neoplasms / chemically induced*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology*
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology*
  • T-Lymphocyte Subsets / transplantation

Substances

  • Receptors, Antigen, T-Cell, alpha-beta