Related Experiment Video
Updated: Nov 7, 2025
Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine
Published on: February 24, 2023
How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma
Mariarosaria Marseglia1, Adriana Amaro1, Nicola Solari1
1IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.
Abstract:
Uveal melanoma (UM), though a rare form of melanoma, is the most common intraocular tumor in adults. Conventional therapies of primary tumors lead to an excellent local control, but 50% of patients develop metastases, in most cases with lethal outcome. Somatic driver mutations that act on the MAP-kinase pathway have been identified, yet targeted therapies show little efficacy in the clinics. No drugs are currently available for the G protein alpha subunitsGNAQ and GNA11, which are the most frequent driver mutations in UM. Drugs targeting the YAP-TAZ pathway that is also activated in UM, the tumor-suppressor gene BRCA1 Associated Protein 1 (BAP1) and the Splicing Factor 3b Subunit 1 gene (SF3B1) whose mutations are associated with metastatic risk, have not been developed yet. Immunotherapy is highly effective in cutaneous melanoma but yields only poor results in the treatment of UM: anti-PD-1 and anti-CTLA-4 blocking antibodies did not meet the expectations except for isolated cases. Here, we discuss how the improved knowledge of the tumor microenvironment and of the cross-talk between tumor and immune cells could help to reshape anti-tumor immune responses to overcome the intrinsic resistance to immune checkpoint blockers of UM. We critically review the dogma of low mutational load, the induction of immune-suppressive cells, and the expression of alternative immune checkpoint molecules. We argue that immunotherapy might still be an option for the treatment of UM.
Insights
Uveal melanoma (UM) is a rare eye cancer with poor treatment options. Understanding the tumor microenvironment may help overcome resistance to immunotherapy, offering new hope for patients with this aggressive disease.
Area of Science:
- Ophthalmology
- Oncology
- Immunology
Background:
- Uveal melanoma (UM) is the most common adult intraocular tumor, with conventional therapies offering poor systemic control and high metastatic rates.
- Despite identified driver mutations (e.g., GNAQ, GNA11) and activated pathways (YAP-TAZ), targeted therapies and immunotherapy (anti-PD-1, anti-CTLA-4) show limited efficacy in UM.
- Mutations in BRCA1 Associated Protein 1 (BAP1) and Splicing Factor 3b Subunit 1 (SF3B1) are linked to metastatic risk, but drugs targeting these are undeveloped.
Purpose of the Study:
- To review current knowledge of the uveal melanoma tumor microenvironment and its impact on immune cell interactions.
- To explore strategies for reshaping anti-tumor immune responses to overcome UM's resistance to immunotherapy.
- To critically evaluate factors contributing to UM's poor response to immune checkpoint blockers.
Main Methods:
- Literature review and critical analysis of existing research on uveal melanoma.
- Discussion of tumor microenvironment components and their role in immune evasion.
- Examination of genetic mutations, pathway activations, and their therapeutic implications.
Main Results:
- Conventional UM therapies achieve local control but fail to prevent frequent, lethal metastases.
- Targeted therapies for common UM mutations (GNAQ, GNA11) are lacking, and immunotherapy shows minimal success.
- The tumor microenvironment, immune cell cross-talk, low mutational load dogma, immune-suppressive cells, and alternative checkpoints influence UM's treatment resistance.
Conclusions:
- Improved understanding of the UM tumor microenvironment is crucial for developing effective immunotherapies.
- Strategies to overcome immune resistance, including addressing immune-suppressive factors and alternative checkpoints, are needed.
- Despite current challenges, immunotherapy holds potential for uveal melanoma treatment with further research and tailored approaches.
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