TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer

// Yinan Yao 1, * , Hequan Li 1, * , Junjun Chen 1 , Weiyi Xu 2 , Guangdie Yang 1 , Zhang Bao 1 , Dajing Xia 3, 4 , Guohua Lu 1 , Shuwen Hu 1 , Jianying Zhou 1 1 Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China 2 Department of Clinical Laboratory, First Affiliated Hospital of Zhejiang University, Hangzhou, China 3 School of Public Health, Zhejiang University, Institute of Immunology, Zhejiang University, Hangzhou, China 4 Institute of Immunology, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Jianying Zhou, email: zjyhz@zju.edu.cn Hequan Li, email: lihequan@zju.edu.cn Keywords: TREM-2, lung cancer, IL-10, Syk, immunoregulation Received: October 20, 2015     Accepted: March 28, 2016     Published: April 18, 2016 ABSTRACT 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 (CD80 Low CD86 Low MHCII Low ) 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.