Molecular analysis of tumor-promoting CD8+ T cells in two-stage cutaneous chemical carcinogenesis

J Invest Dermatol. 2010 Jun;130(6):1726-36. doi: 10.1038/jid.2009.362. Epub 2009 Nov 19.

Abstract

T-pro are tumor-infiltrating TCRalphabeta(+)CD8(+) cells of reduced cytotoxic potential that promote experimental two-stage chemical cutaneous carcinogenesis. Toward understanding their mechanism of action, this study uses whole-genome expression analysis to compare T-pro with systemic CD8(+) T cells from multiple groups of tumor-bearing mice. T-pro show an overt T helper 17-like profile (high retinoic acid-related orphan receptor-(ROR)gammat, IL-17A, IL-17F; low T-bet and eomesodermin), regulatory potential (high FoxP3, IL-10, Tim-3), and transcripts encoding epithelial growth factors (amphiregulin, Gro-1, Gro-2). Tricolor flow cytometry subsequently confirmed the presence of TCRbeta(+) CD8(+) IL-17(+) T cells among tumor-infiltrating lymphocytes (TILs). Moreover, a time-course analysis of independent TIL isolates from papillomas versus carcinomas exposed a clear association of the "T-pro phenotype" with malignant progression. This molecular characterization of T-pro builds a foundation for elucidating the contributions of inflammation to cutaneous carcinogenesis, and may provide useful biomarkers for cancer immunotherapy in which the widely advocated use of tumor-specific CD8(+) cytolytic T cells should perhaps accommodate the cells' potential corruption toward the T-pro phenotype. The data are also likely germane to psoriasis, in which the epidermis may be infiltrated by CD8(+) IL-17-producing T cells.

Publication types

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

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / adverse effects
  • Amphiregulin
  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Differentiation
  • Disease Models, Animal
  • EGF Family of Proteins
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling*
  • Glycoproteins / metabolism
  • Hepatitis A Virus Cellular Receptor 2
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-17 / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Receptors, Virus / metabolism
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology*

Substances

  • Amphiregulin
  • Areg protein, mouse
  • EGF Family of Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glycoproteins
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-17
  • Receptors, Antigen, T-Cell, alpha-beta
  • Receptors, Virus
  • Interleukin-10
  • 9,10-Dimethyl-1,2-benzanthracene