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 (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.
Highlights
Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death worldwide, presenting a rapid increase of incidence and stubbornly high mortality [1]
We found that the number of triggering receptor expressed on myeloid cells-2 (TREM-2)+monocytes in peripheral blood and the mean fluorescence intensity (MFI) of its expression significantly increased in the lung cancer patients and tumor-bearing mice compared to that in healthy controls (Figure 1A, 1B)
Recent studies found that TREM-2 paired with DNAX-activation protein 12 (DAP12) had a critical role in the negative regulation of dendritic cells (DCs) and MΦ activation upon Tolllike receptor (TLR) ligation [9, 10, 13, 14]
Summary
Lung cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death worldwide, presenting a rapid increase of incidence and stubbornly high mortality [1]. More recent evidences have argued for a negative regulatory mechanism that serve to impede the ongoing immune responses, which give a new hope for cancer therapy. Current evidence proved that TREM-2-deficient BM-derived DCs produced increased inflammatory cytokine and type I interferon (IFN) in response to Tolllike receptor (TLR) agonists, and were more efficient at inducing antigen-specific T-cell proliferation [9]. Tumor necrosis factor (TNF)-α and IL-6 levels were higher in TREM-2 deficient BM-derived MΦs in response to TLR ligands [10]. These studies indicated that TREM2 negatively regulated TLR responses in DCs and MΦs during inflammation, which led us to speculate that TREM-2 may exert a similar role in the antitumor immunity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
