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Checkpoint Blockade Efficacy in Uveal Melanoma Is Linked to Tumor Immunity, CD28, and CCL8
Elias A T Koch1, Renato Liguori2,3, Alejandro Afonso Castro1
1Department of Dermatology, Deutsches Zentrum Immuntherapie (DZI), CCC Erlangen-EMN, Bavarian Cancer Research Center (BZKF), Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany.
Abstract:
For patients with metastatic uveal melanoma (UM), tebentafusp is currently the only systemic therapy approved by the EMA and FDA, but its use is limited to HLA-A*02:01-positive individuals. Immune checkpoint blockade (ICB) represents another option, though only a small subgroup of patients benefits, and no reliable predictive biomarkers are available to date. The aim of this study was therefore to identify parameters associated with favorable ICB response. Tumor samples and clinical data from 30 patients were analyzed. Group A (n = 16) showed clinical benefit, while Group B (n = 14) experienced disease progression. NanoString® analyses revealed 258 upregulated genes in Group A, including IDO1, CD28, and CCL8. The enriched pathways were predominantly linked to immune activation, leukocyte adhesion, and responses to external stimuli. Immunohistochemistry confirmed significantly higher CD28 expression on infiltrating immune cells in Group A, while a machine learning approach identified CCL8 as a predictive marker with ~78% accuracy. Overall survival differed significantly between the groups. These findings indicate that patients responding to ICB display tumors with enhanced immune activation. CD28 and CCL8 emerged as promising candidates and should be validated in prospective studies to determine their clinical utility.
Insights
Immune checkpoint blockade (ICB) shows promise for metastatic uveal melanoma (UM) patients. This study identified CD28 and CCL8 as key biomarkers predicting response to ICB therapy in UM.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Metastatic uveal melanoma (UM) treatment options are limited, with tebentafusp approved only for HLA-A*02:01-positive patients.
- Immune checkpoint blockade (ICB) offers potential but lacks predictive biomarkers for patient selection.
Purpose of the Study:
- To identify parameters associated with favorable immune checkpoint blockade (ICB) response in metastatic uveal melanoma (UM).
Main Methods:
- Analysis of tumor samples and clinical data from 30 UM patients categorized by response to ICB (benefit vs. progression).
- NanoString® gene expression analysis to identify upregulated genes and enriched pathways.
- Immunohistochemistry to assess CD28 expression and machine learning for predictive marker identification.
Main Results:
- NanoString® analysis revealed 258 upregulated genes in responders, including IDO1, CD28, and CCL8, with pathways linked to immune activation.
- Significantly higher CD28 expression on immune cells was observed in responding patients.
- CCL8 was identified as a predictive marker for ICB response with approximately 78% accuracy.
Conclusions:
- Patients responding to ICB exhibit tumors with enhanced immune activation.
- CD28 and CCL8 are promising biomarkers for predicting ICB response in UM.
- Further prospective studies are needed to validate the clinical utility of CD28 and CCL8.
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