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Tumour‐mediated disruption of dendritic cell function: Inhibiting the MEK1/2‐p44/42 axis restores IL‐12 production and Th1‐generation
Author(s) -
Jackson Andrew Mark,
Mulcahy Lori Ann,
Zhu Xing Wu,
O'Donnell Dearbhaile,
Patel Poulam M.
Publication year - 2008
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23530
Subject(s) - mapk/erk pathway , cd80 , immune system , cancer research , dendritic cell , immunotherapy , cancer immunotherapy , adoptive cell transfer , biology , t cell , cd86 , protein kinase a , kinase , microbiology and biotechnology , immunology , cd40 , cytotoxic t cell , biochemistry , in vitro
Disfunctional dendritic cells (DC) are common in cancer patients; however, the underlying molecular targets are poorly understood. Nevertheless, adoptive‐transfer and in situ vaccination protocols continue, largely without addressing immune‐suppression. Understanding tumour‐mediated DC suppression would assist rational design of next generation immunotherapy. This study used a tumour‐lysate loaded DC model of adoptive immunotherapy and also necrotic cells common in many tumours. Patient‐derived and healthy‐donor monocyte‐derived DC were examined for disruptions in mitogen‐activated protein kinase (MAPK) signalling pathways associated with their capacity to generate Type‐1 helper‐T cell populations (Th1). Melanoma‐lysate markedly suppressed TLR4‐dependent IL‐12p40 and p70 production. Suppression of IL‐12p70 occurred independently of maturation markers ( e.g ., CD40, CD80, CD83) and correlated with depressed p35 and p40 transcription. Decreased IL‐12 secretion was not associated with IL‐10, TGFβ, VEGF, PGE 2 or ganglioside in tumour lysates or attributable to endogenous PGE 2 release from DC. In contrast to HUVEC lysate, melanoma‐lysate‐treated DC were less able to generate Th1‐responses from naïve T‐cells. The p44/42 MAPK was hyper‐activated by melanoma lysate, but not that of HUVEC. Blockade of MEK1/2, the upstream kinase for p44/42, with U0126 prevented p44/42 activation, restored IL‐12p70, and permitted effective generation of Th1‐responses. Therefore the p44/42 MAPK is a target for tumour‐mediated immune suppression of DC resulting in transcriptional down‐regulation of IL‐12 p35 and p40 genes, reduced IL‐12 secretion and suppressed Th1‐responses. Pharmacological intervention in the MEK‐p44/42 axis may be applicable to render DC resistant to the suppressive effects of tumour lysates and may form part of a combination immunotherapy. © 2008 Wiley‐Liss, Inc.