TREM2: Exploring Its Role in Tumor-Associated Macrophages and Cancer Immunotherapy

In the TME, TREM2 is upregulated on tumor-associated macrophages (TAMs), where it plays a crucial role in maintaining an immunosuppressive environment. TAMs expressing TREM2 produce anti-inflammatory cytokines like IL-10 and TGF-β, which inhibit the activity of cytotoxic T cells and natural killer (NK) cells that are essential for anti-tumor immunity. TREM2 also promotes the recruitment of regulatory immune cells, such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), further enhancing immune suppression in the TME.

Increased TREM2 expression is associated with poor prognosis in several cancers, including:

• Liver cancer
• Pancreatic cancer
• Non-small cell lung cancer (NSCLC)

These findings underscore the potential of TREM2 as a therapeutic target to counteract TAM-mediated immune suppression in cancer.

Targeting TREM2 in TAMs offers a promising strategy to disrupt the immunosuppressive environment in tumors. By inhibiting TREM2, therapies aim to reprogram TAMs from an immunosuppressive M2-like phenotype to a pro-inflammatory M1-like state, promoting anti-tumor immunity through mechanisms such as:

• Increased cytokine production: Blocking TREM2 can enhance the production of pro-inflammatory cytokines like IL-12 and TNF-α, which support the recruitment and activation of T cells and NK cells within the tumor.
• Enhanced phagocytosis and antigen presentation: TREM2 inhibition can improve the ability of TAMs to present tumor antigens, enhancing T cell recognition of cancer cells.
• Reduction in immunosuppressive cells: TREM2-targeted therapies can decrease the recruitment of MDSCs and Tregs, further reducing immune suppression in the TME.

These shifts in the TME create a more immunogenic environment, allowing immune cells to mount an effective response against the tumor.

Monoclonal antibodies designed to block TREM2 signaling are currently being evaluated for their ability to modulate TAM activity and enhance anti-tumor immunity. The mechanism of action of TREM2-targeting antibodies involves:

1. Direct inhibition of TREM2: Blocking TREM2 signaling prevents the receptor from promoting immunosuppressive functions in TAMs.
2. Activation of pro-inflammatory pathways: TREM2 inhibition shifts TAMs from an M2-like to an
   M1-like phenotype, increasing their ability to produce inflammatory cytokines and support anti-tumor responses.
3. Improved T cell and NK cell activation: With reduced immune suppression, T cells and NK cells
   can more effectively infiltrate the tumor and engage in cytotoxic
   activity.

By selectively targeting TREM2, these therapies aim to reduce immunosuppression without broadly activating the immune system, thus minimizing the risk of systemic side effects.

TREM2-targeting therapies hold potential across various cancer types where TAM-mediated immune suppression plays a major role. These include:

• Hepatocellular carcinoma (HCC): High levels of TREM2-positive TAMs are often observed in liver cancer, contributing to immune evasion and resistance to treatment.
• Pancreatic cancer: TREM2-expressing TAMs are prominent in the pancreatic tumor microenvironment, where they enhance tumor growth and limit immune cell infiltration.
• Non-Small Cell Lung Cancer (NSCLC): TREM2 expression on TAMs in NSCLC is associated with poor prognosis, making it a promising target for enhancing the effectiveness of immunotherapy.

Checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4, are standard therapies in cancer treatment, designed to release inhibitory signals that limit T cell activation. However, the immunosuppressive activity of TAMs, including TREM2-expressing TAMs, can limit the effectiveness of these therapies. Targeting TREM2 complements checkpoint inhibition by reducing the suppressive influence of TAMs, thereby enhancing the immune response within the TME.

• Enhanced T cell activation: TREM2 blockade reduces TAM-mediated immune suppression, enabling checkpoint inhibitors to activate T cells more effectively.
• Overcoming resistance: Tumors resistant to checkpoint inhibitors alone may respond to the combined targeting of TREM2 and PD-1/PD-L1 or CTLA-4, promoting a more comprehensive anti-tumor response.         

CAR-T cell therapy is a breakthrough treatment for hematologic cancers, but its effectiveness in solid tumors has been limited by the immunosuppressive TME. Targeting TREM2 could help overcome this barrier by reducing TAM-mediated suppression, allowing CAR-T cells to survive and function more effectively within the TME.

While TREM2-targeting therapies offer a promising approach to reduce immune suppression in the TME, blocking TREM2 may also lead to immune-related adverse events (irAEs), such as inflammation in normal tissues. Selecting the appropriate dose and identifying biomarkers to predict patient response will be critical in minimizing potential toxicities while maximizing therapeutic efficacy.

Ongoing research on TREM2-targeted therapies will likely expand their application across additional tumor types with high levels of TAM-mediated immune suppression. Biomarkers that predict TREM2 expression levels in tumors will be essential for patient selection and optimizing personalized cancer therapy.

TREM2 plays a central role in maintaining immunosuppressive tumor-associated macrophages (TAMs) within the tumor microenvironment, contributing to immune evasion and tumor progression. By targeting TREM2 with therapies designed to shift TAMs from an immunosuppressive to a pro-inflammatory, anti-tumor phenotype, cancer immunotherapy has the potential to enhance immune cell activity, reduce immune suppression, and improve treatment outcomes. As research into TREM2-targeted therapies advances, they hold great promise for expanding the effectiveness of immunotherapies, particularly in cancers with high levels of TAM infiltration.

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