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Platinum-Based TREM2 Inhibitor Suppresses Tumors by Remodeling the Immunosuppressive Microenvironment

Tao Yang1,2, Shuren Zhang1,2, Hao Yuan1

  • 1State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, P. R. China.

Angewandte Chemie (International Ed. in English)
|October 19, 2022
PubMed

Insights

A novel platinum(IV) complex, OPA, inhibits TREM2 (triggering receptor expressed on myeloid cells-2) on immunosuppressive macrophages. This chemoimmunotherapeutic agent reduces tumor growth and enhances anti-cancer immunity.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Triggering receptor expressed on myeloid cells-2 (TREM2) is a pro-tumorigenic marker on tumor-infiltrating macrophages.
  • TREM2 exhibits immunosuppressive activity within the tumor microenvironment, hindering anti-cancer immune responses.

Purpose of the Study:

  • To investigate the potential of a novel platinum(IV) complex, OPA, as a TREM2 inhibitor.
  • To evaluate OPA's efficacy in modulating the tumor microenvironment and enhancing anti-cancer immunity.

Main Methods:

  • Synthesis and characterization of the platinum(IV) complex OPA.
  • In vitro and in vivo assessment of OPA's cytotoxicity and immunomodulatory effects.
  • Evaluation of OPA's impact on macrophage populations (CD206+, CX3CR1+) and immune cell infiltration in a colorectal tumor mouse model.

Main Results:

  • OPA demonstrated direct cytotoxicity against human colon cancer cells.
  • OPA effectively inhibited TREM2 on macrophages in vitro and in vivo.
  • OPA reduced the number of immunosuppressive macrophages and promoted the infiltration of immunostimulatory dendritic cells, cytotoxic T cells, and natural killer cells.
  • OPA deterred tumor growth in a mouse model of colorectal cancer.

Conclusions:

  • OPA is the first small-molecule TREM2 inhibitor identified.
  • OPA effectively relieves the immunosuppressive tumor microenvironment.
  • OPA enhances the anti-cancer efficacy of platinum-based chemotherapy, exhibiting characteristics of a chemoimmunotherapeutic agent.
Keywords:
TREM2 inhibitorchemoimmunotherapeutic agentimmunosuppressionplatinum drugtumor microenvironment

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