TREM2: Exploring Its Role in Tumor-Associated Macrophages and Cancer Immunotherapy
Introduction to TREM2 and Tumor-Associated Macrophages in Cancer
TREM2 (triggering receptor expressed on myeloid cells 2) is an immunoregulatory receptor primarily expressed on macrophages, microglia, monocytes, and dendritic cells. In the context of cancer, TREM2 is highly expressed on tumor-associated macrophages (TAMs), a major immune cell population in the tumor microenvironment (TME) that supports tumor growth and immune evasion. TREM2 signaling in TAMs promotes immunosuppressive functions, limiting the ability of the immune system to recognize and destroy cancer cells.
Research has shown that blocking TREM2 can shift TAMs from an immunosuppressive state to a more pro-inflammatory, anti-tumor phenotype, improving the immune response against tumors. This has made TREM2 a compelling target in cancer immunotherapy, offering new avenues to enhance anti-tumor immunity, especially in cancers where TAMs play a significant role in promoting tumor progression.
This article explores the biology of TREM2, its role in TAM-mediated immune suppression, and the potential of TREM2-targeted therapies in cancer treatment.
TREM2: Structure, Expression, and Immune Function
The Role of TREM2 in Immune Regulation
TREM2 is a receptor expressed on myeloid cells, particularly on macrophages and microglia, where it modulates immune responses by recognizing lipid molecules, apoptotic cells, and pathogen-associated patterns. Activation of TREM2 signaling influences multiple aspects of macrophage function:
- Promotion of phagocytosis: TREM2 activation enhances the ability of macrophages to clear apoptotic cells and debris, contributing to tissue repair.
- Regulation of inflammatory responses: TREM2 signaling generally limits pro-inflammatory cytokine production, promoting immune tolerance and preventing chronic inflammation.
- Support of immunosuppressive macrophages: TREM2-positive macrophages tend to exhibit an M2-like or immunosuppressive phenotype, which limits immune activation in the TME.
In cancer, these immunosuppressive functions are often co-opted by tumors to create an environment that allows for immune escape and tumor progression.
TREM2 Expression in Tumor-Associated Macrophages
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:
These findings underscore the potential of TREM2 as a therapeutic target to counteract TAM-mediated immune suppression in cancer.
TREM2 as a Therapeutic Target in Cancer Immunotherapy
Shifting TAMs to an Anti-Tumor Phenotype
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.
TREM2-Targeting Agents in Development
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:
- Direct inhibition of TREM2: Blocking TREM2 signaling prevents the receptor from promoting immunosuppressive functions in TAMs.
- 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. - 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.
Potential Clinical Applications of TREM2-Targeting Therapies
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.
Cancer Type | TREM2 Expression in TAMs | Therapeutic Potential of TREM2 Blockade |
---|---|---|
High in TME | TREM2 blockade can shift TAMs to an anti-tumor phenotype, improving immune activation. | |
Prominent TREM2-positive TAM population | Targeting TREM2 can enhance T cell and NK cell responses against the tumor. | |
Elevated in immunosuppressive TAMs | TREM2 inhibition may reduce immune suppression, enhancing the efficacy of checkpoint inhibitors. |
Synergy with Other Immunotherapies
Combination with Checkpoint Inhibitors
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.
Potential for Combination with CAR-T Cell Therapy
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.
Challenges and Future Directions in TREM2-Targeted Therapy
Managing Immune-Related Toxicities
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.
Expanding Applications and Personalized Cancer Therapy
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.
Conclusion
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.
References
- Colonna, M., Wang, Y., 2016. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nature Reviews Neuroscience, 17(4), pp.201-207.
- Mass, E., et al., 2016. A somatic map of the human TREM2 macrophage landscape. Nature, 538(7624), pp.368-372.
- Lo, H., et al., 2021. TREM2 in the tumor microenvironment: immunomodulation and beyond. Journal of Clinical Investigation, 131(2), e142738.
- Molgora, M., et al., 2019. TREM2 regulates anti-tumor macrophage response. Nature Immunology, 20(9), pp.1201-1214.
- Klesney-Tait, J., Turnbull, I.R., Colonna, M., 2006. The TREM receptor family and signal integration. Nature Immunology, 7(12), pp.1266-1273.
- Saxton, R.A., et al., 2018. Regulation of immune checkpoint receptors in the tumor microenvironment. Annual Review of Cancer Biology, 2(1), pp.501-524.
- March, O., et al., 2020. Therapeutic blockade of TREM2 enhances anti-tumor immunity by modulating TAMs. Frontiers in Oncology, 10, p.676.
- Wu, X., et al., 2021. TREM2: a critical immunoregulator in cancer immunotherapy. Trends in Immunology, 42(9), pp.800-814.
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