LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses.
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.
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine;
Feng
F
Xu
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine;
Jing
J
Liu
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine;
Di
D
Liu
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine;
Biao
B
Liu
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine;
Min
M
Wang
National Center for Nanoscience and Technology;
Zhiyuan
Z
Hu
Department of Pathology, Capital Medical University affiliated Beijing Shijitan Hospital;
Xuemei
X
Du
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine; tangli08@aliyun.com hefc@nic.bmi.ac.cn.
Li
L
Tang
Authors' Affiliations: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine; College of Life Sciences, Peking University; and Department of Biology Sciences and Biotechnology, Tsinghua University, Beijing, China tangli08@aliyun.com hefc@nic.bmi.ac.cn.
Fuchu
F
He
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis / Q000378:metabolism*; D008212:Lymphocyte Depletion; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011991:Receptors, Virus / Q000096:biosynthesis / Q000378:metabolism*; D019139:Tumor Escape / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C561095:LSECtin protein, mouse; D037181:Lectins, C-Type; D011991:Receptors, Virus; D007371:Interferon-gamma; C495893:Cdk2 protein, mouse; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D000093322:Lymphocyte Activation Gene 3 Protein