期刊
CANCER RESEARCH
卷 74, 期 13, 页码 3418-3428出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2690
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资金
- Chinese National Natural Science Foundation Projects [31270953]
- Chinese State Key Program in Basic Research [2010CB911902, 2013CB910802, 2013ZX10002009]
- Chinese National High-tech Program [2012AA020206-2]
Therapeutic antibodies that target T-cell co-inhibitory molecules display potent antitumor effects in multiple types of cancer. LSECtin is a cell surface lectin of the DC-SIGN family expressed in dendritic cells that inhibits T-cell responses. LSECtin limits T-cell activity in infectious disease, but it has not been studied in cancer. Here we report the finding that LSECtin is expressed commonly in melanomas where it blunts tumor-specific T-cell responses. When expressed in B16 melanoma cells, LSECtin promoted tumor growth, whereas its blockade slowed tumor growth in either wild-type or LSECtin-deficient mice. The tumor-promoting effects of LSECtin were abrogated in Rag1(-/-) mice or in response to CD4(+) or CD8(+) T-cell depletion. Mechanistic investigations determined that LSECtin inhibited the proliferation of tumor-specific effector T cells by downregulating the cell cycle kinases CDK2, CDK4, and CDK6. Accordingly, as expressed in B16, tumor cells LSECtin inhibited tumorspecific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the coregulatory molecule LAG-3, the blockade of which restored IFN gamma secretion that was reduced by melanoma-derived expression of LSECtin. Together, our findings reveal that common expression of LSECtin in melanoma cells engenders a mechanism of immune escape, with implications for novel immunotherapeutic combination strategies. (C) 2014 AACR.
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