LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses

Cancer Res. 2014 Jul 1;74(13):3418-28. doi: 10.1158/0008-5472.CAN-13-2690. Epub 2014 Apr 25.

Abstract

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 tumor-specific T-cell responses relying upon proliferation in vitro and in vivo. Notably, LSECtin interacted with the co-regulatory molecule LAG-3, the blockade of which restored IFNγ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclin-Dependent Kinase 2 / biosynthesis
  • Cyclin-Dependent Kinase 4 / biosynthesis
  • Cyclin-Dependent Kinase 6 / biosynthesis
  • Dendritic Cells / immunology
  • Down-Regulation
  • Female
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / metabolism
  • Lectins, C-Type / biosynthesis
  • Lectins, C-Type / metabolism*
  • Lymphocyte Depletion
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Virus / biosynthesis
  • Receptors, Virus / metabolism*
  • Tumor Escape / immunology

Substances

  • Antigens, CD
  • CD223 antigen
  • LSECtin protein, mouse
  • Lectins, C-Type
  • Receptors, Virus
  • Interferon-gamma
  • Cdk2 protein, mouse
  • Cdk4 protein, mouse
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6