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.

e22054 Background: More recent evidences have argued that negative regulatory mechanism that serve to impede ongoing immune responses, which gain in interest as a complementary strategy for cancer therapy. Triggering receptor expressed on myeloid cells-2 (TREM-2) restrains phagocytosis of both dendritic cells (DCs) and macrophages(MΦs), and reduces release of inflammatory cytokines through DAP12-mediated inhibitory signal, prompting us to investigate the role of TREM-2 involved in immune dysfunction among tumor-bearing host. Methods: In lung cancer patients, monocytes of peripheral blood were analyzed by flow cytometry and MΦs around tumour cells in lung tissue were detected by immunehistochemistry. Then we prepared conditional medium containing supernatant of 3LL cells mimicing tumor microenvironment for DC and MΦ derivation, and established an orthotopic lung cancer-bearing mice model to explore the further mechanism. Results: It was showed that TREM-2 expression on monocytes was up-regulated in lung cancer patients compared with that of healthy controls, and that TREM-2 levels of macrophages had a positive correlation with TNM stage. Moreover, reduction of tumor burden, by operation or chemotherapy, led to obvious decline of TREM-2 expression. The percentage of TREM-2+DC in the murine lung significantly increased after tumor-bearing, and such DCs preformed lower MHCII-Ia, CD86 expression, and IL-12 production, but higher IL-10 secretion. In vitro, more TREM-2+DCs and TREM-2+MΦs were harvested from ‘conditional’ medium instead of ‘normal’ medium. Also, TREM-2+DCs rather than TREM-2- DCs markedly inhibited proliferation of T cells, which could be partially abolished by anti-TREM-2 mAb. Conclusions: TREM-2 acts as a negative immune regulator in promoting lung cancer progress. Our study provides new mechanism for tumor immune escape and inhibitory checkpoint for immunotherapy.