TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer.
During infection, triggering receptor expressed on myeloid cells-2 (TREM-2) restrains dendritic cells (DCs) and macrophages (MΦs) phagocytosis, as well as reduces pro-inflammatory cytokines release through DNAX-activation protein 12 (DAP12) signaling. However, the role of TREM-2 signaling in cancer has never been elucidated. In the current study, we found that TREM-2 was up-regulated on peripheral blood monocytes in tumor-bearing host. More TREM-2+DCs were detected in the lung of 3LL tumor-bearing mice. On the other hand, the level of TREM-2 on pulmonary MΦs positively correlated with the pathological staging of lung cancer. However, surgical or chemotherapeutic reduction of tumor burden led to the obvious decline of TREM-2. In vitro, TREM-2 expression of bone marrow (BM)-derived DCs and MΦs was induced by conditional medium (CM) containing the supernatant of 3LL cells. TREM-2+DCs from CM and/or tumor-bearing mice held altered phenotypes (CD80LowCD86LowMHCIILow) and impaired functions, such as, reduced interleukin (IL)-12 secretion, increased IL-10 production, and weakened ovalbumin (OVA)-endocytic capacity; also developed potent inhibitory effect on T cell proliferation that could be partially reversed by TREM-2 blockage. Moreover, spleen tyrosine kinase (Syk) inhibitor restrained IL-10 production of TREM-2+DC. Remarkably, IL-10 neutralizing antibody and Syk inhibitor both lowered the suppressive potential of TREM-2+DCs in T cell proliferation. Also, adoptive transfer of this TREM-2+DCs accelerated the tumor growth rather than jeopardized survival in lung cancer-bearing mice. In conclusion, these results indicate that TREM-2 might act as a negative immuno-regulatory molecule through Syk pathway in an IL-10 dependent manner and partially predicts prognosis in lung cancer patients.
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Yinan
Y
Yao
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Hequan
H
Li
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Junjun
J
Chen
Department of Clinical Laboratory, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Weiyi
W
Xu
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Guangdie
G
Yang
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Zhang
Z
Bao
School of Public Health, Zhejiang University, Institute of Immunology, Zhejiang University, Hangzhou, China.|Institute of Immunology, Zhejiang University, Hangzhou, China.
Dajing
D
Xia
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Guohua
G
Lu
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Shuwen
S
Hu
Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.
Jianying
J
Zhou
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism*; D000072377:Syk Kinase / Q000276:immunology / Q000378:metabolism*
D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C498716:Trem2 protein, mouse; D016753:Interleukin-10; D000072377:Syk Kinase
IL-10; Syk; TREM-2; immunoregulation; lung cancer