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Targeting the cMET pathway to enhance immunotherapeutic approaches for mUM patients
Devayani Machiraju1, Jessica C Hassel1
1Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany.
Abstract:
The liver is the most preferential initial site of metastasis for uveal melanoma (mUM), and this preference is associated with rapid mortality in mUM patients. Despite the significant clinical benefits of Immune checkpoint inhibitors (ICIs) in metastatic cutaneous melanoma patients, ICIs have shown little to no benefit in mUM patients. A potential reason for this inefficiency of ICI could be partly devoted to the involvement of the liver itself, thanks to its rich source of growth factors and immunosuppressive microenvironment. Uveal melanoma cells show increased expression of a transmembrane protein called cMET, which is known as the sole receptor for the Hepatocyte growth factor (HGF). Hyperactivation of cMET by HGF contributes to mUM development, and the liver, being the major source of HGF, may partially explain the metastasis of uveal melanoma cells to the liver. In addition, cMET/HGF signaling has also been shown to mediate resistance to ICI treatment, directly and indirectly, involving tumor and immune cell populations. Therefore, targeting the cMET/HGF interaction may enhance the efficacy of immunotherapeutic regimes for mUM patients. Hence in this minireview, we will discuss the rationale for combining cMET inhibitors/antibodies with leading immune checkpoint inhibitors for treating mUM. We will also briefly highlight the challenges and opportunities in targeting cMET in mUM.
Insights
Targeting cMET/HGF signaling may improve immune checkpoint inhibitor (ICI) efficacy in uveal melanoma (UM) liver metastasis. Combining cMET inhibitors with ICIs offers a promising strategy for treating this aggressive cancer.
Area of Science:
- Oncology
- Immunotherapy
- Melanoma Research
Background:
- Uveal melanoma (UM) frequently metastasizes to the liver, leading to poor patient outcomes.
- Immune checkpoint inhibitors (ICIs) show limited efficacy in metastatic UM (mUM), potentially due to the liver's immunosuppressive microenvironment.
- Hepatocyte growth factor (HGF) and its receptor cMET are upregulated in UM and implicated in liver metastasis and ICI resistance.
Purpose of the Study:
- To review the rationale for combining cMET inhibitors with ICIs in mUM.
- To explore the role of cMET/HGF signaling in mUM liver metastasis and ICI resistance.
- To discuss challenges and opportunities in targeting cMET for mUM treatment.
Main Methods:
- Literature review of studies on cMET/HGF signaling in UM.
- Analysis of the interplay between the liver microenvironment, cMET/HGF, and immune responses.
- Examination of preclinical and clinical data on cMET inhibitors and ICIs in melanoma.
Main Results:
- The liver's microenvironment promotes mUM metastasis via HGF/cMET signaling.
- cMET/HGF pathway activation contributes to resistance against ICIs in mUM.
- Targeting cMET may overcome resistance mechanisms and enhance anti-tumor immunity.
Conclusions:
- Combining cMET inhibitors with ICIs presents a viable therapeutic strategy for mUM.
- Further research is needed to optimize combination therapies and address challenges in cMET targeting.
- This approach holds potential to improve survival rates for mUM patients with liver metastasis.
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