Molecular analysis of tumor-promoting CD8+ T cells in two-stage cutaneous chemical carcinogenesis.
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.
Kwong
Bernice Y
BY
Department of Dermatology and Skin Diseases Research Center, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Roberts
Scott J
SJ
Silberzahn
Tobias
T
Filler
Renata B
RB
Neustadter
Jason H
JH
Galan
Anjela
A
Reddy
Swapna
S
Lin
William M
WM
Ellis
Peter D
PD
Langford
Cordelia F
CF
Hayday
Adrian C
AC
Girardi
Michael
M
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D066258:Amphiregulin; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000378:metabolism; D000072597:Hepatitis A Virus Cellular Receptor 2; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*
D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D036341:Intercellular Signaling Peptides and Proteins; D020381:Interleukin-17; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011991:Receptors, Virus; D016753:Interleukin-10; D015127:9,10-Dimethyl-1,2-benzanthracene