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Updated: Jul 24, 2025
Author Spotlight: Exploring Strategies for Successful Immune Response Against Tumors
Published on: August 16, 2024
Single-cell dissection of Merkel cell carcinoma heterogeneity unveils transcriptomic plasticity and therapeutic
Bhaba K Das1, Aarthi Kannan2, Graham J Velasco3
1Southern California Institute for Research and Education, Long Beach, CA 90822, USA.
Abstract:
Merkel cell carcinoma (MCC), a rare but aggressive skin cancer, remains a challenge in the era of precision medicine. Immune checkpoint inhibitors (ICIs), the only approved therapy for advanced MCC, are impeded by high primary and acquired resistance. Hence, we dissect transcriptomic heterogeneity at single-cell resolution in a panel of patient tumors, revealing phenotypic plasticity in a subset of treatment-naive MCC. The tumor cells in a "mesenchymal-like" state are endowed with an inflamed phenotype that portends a better ICI response. This observation is also validated in the largest whole transcriptomic dataset available from MCC patient tumors. In contrast, ICI-resistant tumors predominantly express neuroepithelial markers in a well-differentiated state with "immune-cold" landscape. Importantly, a subtle shift to "mesenchymal-like" state reverts copanlisib resistance in primary MCC cells, highlighting potential strategies in patient stratification for therapeutics to harness tumor cell plasticity, augment treatment efficacy, and avert resistance.
Insights
Merkel cell carcinoma (MCC) exhibits phenotypic plasticity, with a mesenchymal-like state predicting better immune checkpoint inhibitor (ICI) response. Understanding this tumor cell plasticity is key to improving MCC treatment efficacy.
Area of Science:
- Oncology
- Dermatology
- Immunology
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer.
- Immune checkpoint inhibitors (ICIs) are the primary therapy for advanced MCC but face significant resistance.
- Understanding the mechanisms of ICI resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate transcriptomic heterogeneity at single-cell resolution in MCC.
- To identify cellular phenotypes associated with response or resistance to ICIs.
- To explore strategies for overcoming ICI resistance by targeting tumor cell plasticity.
Main Methods:
- Single-cell RNA sequencing of patient-derived MCC tumors.
- Analysis of the largest available whole transcriptomic dataset for MCC.
- Functional assays to assess the impact of phenotypic shifts on drug resistance.
Main Results:
- Identified phenotypic plasticity in treatment-naive MCC.
- A 'mesenchymal-like' state correlates with an inflamed phenotype and better ICI response.
- ICI-resistant tumors display neuroepithelial markers and an 'immune-cold' profile.
- A shift to a 'mesenchymal-like' state reversed resistance to copanlisib in MCC cells.
Conclusions:
- Tumor cell plasticity is a critical factor in MCC response to ICIs.
- The 'mesenchymal-like' phenotype represents a potentially targetable state for enhancing ICI efficacy.
- Harnessing tumor cell plasticity may offer new avenues for patient stratification and therapeutic strategies in MCC.
