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Molecular Analysis of Tumor-Promoting CD8+ T Cells in Two-Stage Cutaneous Chemical Carcinogenesis

2009; Elsevier BV; Volume: 130; Issue: 6 Linguagem: Inglês

10.1038/jid.2009.362

1523-1747

Bernice Y. Kwong, Scott J. Roberts, Tobias Silberzahn, Renata B. Filler, Jason H. Neustadter, Anjela Galan, Swapna Reddy, William M. Lin, Peter Ellis, Cordelia F. Langford, Adrian Hayday, Michael Girardi,

CAR-T cell therapy research

T-pro are tumor-infiltrating TCRαβ+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)γt, 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 TCRβ+ 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. T-pro are tumor-infiltrating TCRαβ+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)γt, 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 TCRβ+ 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. cytolytic T cell 7,12-dimethylbenz[a]anthracene eomesodermin Hanks' Balanced Salt Solution peripheral blood lymphocyte retinoic acid–related orphan receptor T helper tumor-infiltrating lymphocyte 12-O-tetradecanoylphorbol 13-acetate tumor-promoting T cells T-regulatory