Immune evasion by murine melanoma mediated through CC chemokine receptor-10.
Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)-dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.
Dermatology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Takashi
T
Murakami
Adela R
AR
Cardones
Steven E
SE
Finkelstein
Nicholas P
NP
Restifo
Brenda A
BA
Klaunberg
Frank O
FO
Nestle
S Sianna
SS
Castillo
Phillip A
PA
Dennis
Sam T
ST
Hwang
D000368:Aged; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D054447:Receptors, CCR10; D019707:Receptors, Chemokine / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515706:CCR10 protein, human; C515707:Ccr10 protein, mouse; D017931:DNA Primers; D054447:Receptors, CCR10; D019707:Receptors, Chemokine