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

Yinan Yao1, Hequan Li1, Junjun Chen1

  • 1Department of Respiratory Diseases, First Affiliated Hospital of Zhejiang University, Hangzhou, China.

Oncotarget
|April 23, 2016
PubMed

Insights

Triggering receptor expressed on myeloid cells-2 (TREM-2) negatively regulates immune responses in lung cancer. Upregulation of TREM-2 on immune cells impairs their function and promotes tumor growth, suggesting TREM-2 as a potential prognostic marker.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Signaling

Background:

  • Triggering receptor expressed on myeloid cells-2 (TREM-2) normally restrains myeloid cell phagocytosis and pro-inflammatory cytokine release during infection via DNAX-activation protein 12 (DAP12) signaling.
  • The specific role of TREM-2 signaling in the context of cancer, particularly lung cancer, remains largely unelucidated.

Purpose of the Study:

  • To investigate the role and mechanism of TREM-2 signaling in lung cancer.
  • To determine if TREM-2 expression correlates with tumor burden and pathological staging in lung cancer.
  • To assess the functional impact of TREM-2 on dendritic cells (DCs) and macrophages (MΦs) in a tumor-bearing host.

Main Methods:

  • Analysis of TREM-2 expression on peripheral blood monocytes, lung DCs, and pulmonary MΦs in tumor-bearing mice and lung cancer patients.
  • In vitro induction of TREM-2 expression on bone marrow-derived DCs and MΦs using tumor cell-conditioned medium.
  • Functional assays assessing DC/MΦ phenotype, cytokine production (IL-12, IL-10), phagocytic capacity, and T cell proliferation inhibition.
  • Pharmacological inhibition of TREM-2, spleen tyrosine kinase (Syk), and IL-10 neutralization.
  • Adoptive transfer of TREM-2+DCs into tumor-bearing mice.

Main Results:

  • TREM-2 was upregulated on monocytes in tumor hosts and on lung DCs and MΦs, with MΦ expression correlating positively with lung cancer stage.
  • TREM-2+DCs exhibited an immunosuppressive phenotype (CD80LowCD86LowMHCIILow), reduced IL-12, increased IL-10 production, impaired phagocytosis, and suppressed T cell proliferation.
  • Syk inhibition and IL-10 neutralization partially reversed the suppressive function of TREM-2+DCs, and adoptive transfer of these cells accelerated tumor growth.

Conclusions:

  • TREM-2 acts as a negative immuno-regulatory molecule in lung cancer, operating through the Syk pathway in an IL-10-dependent manner.
  • Upregulated TREM-2 on myeloid cells contributes to immune suppression and promotes tumor progression.
  • TREM-2 expression may serve as a prognostic biomarker for lung cancer patients.
Keywords:
IL-10SykTREM-2immunoregulationlung cancer

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