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Updated: Aug 26, 2025
Author Spotlight: Exploring Strategies for Successful Immune Response Against Tumors
Published on: August 16, 2024
Single-cell transcriptomic profiling for inferring tumor origin and mechanisms of therapeutic resistance
Maoxuan Lin1,2, Moshe Sade-Feldman2,3,4, Lori Wirth5
1Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, 02118, USA.
Abstract:
Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive epithelial cancer with poor overall response rates to checkpoint inhibitor therapy (CPI) despite CPI being the recommended treatment for recurrent or metastatic HNSCC. Mechanisms of resistance to CPI in HNSCC are poorly understood. To identify drivers of response and resistance to CPI in a unique patient who was believed to have developed three separate HNSCCs, we performed single-cell RNA-seq (scRNA-seq) profiling of two responding lesions and one progressive lesion that developed during CPI. Our results not only suggest interferon-induced APOBEC3-mediated acquired resistance as a mechanism of CPI resistance in the progressing lesion but further, that the lesion in question was actually a metastasis as opposed to a new primary tumor, highlighting the immense power of scRNA-seq as a clinical tool for inferring tumor origin and mechanisms of therapeutic resistance.
Insights
Checkpoint inhibitor therapy (CPI) shows poor response rates in Head and Neck Squamous Cell Carcinoma (HNSCC). Single-cell RNA-seq identified APOBEC3-mediated resistance and revealed a metastatic origin, not a new primary tumor.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive cancer with limited response to checkpoint inhibitor therapy (CPI).
- Mechanisms underlying CPI resistance in HNSCC remain largely unknown.
- Understanding resistance is crucial for improving treatment outcomes in recurrent or metastatic HNSCC.
Purpose of the Study:
- To investigate the molecular mechanisms of CPI resistance in HNSCC.
- To utilize single-cell RNA-seq (scRNA-seq) to analyze tumor lesions from a patient with suspected multiple HNSCCs.
- To differentiate between primary tumors and metastases and identify drivers of therapeutic resistance.
Main Methods:
- Single-cell RNA-seq (scRNA-seq) profiling was performed on two responding and one progressive HNSCC lesion from a single patient undergoing CPI.
- Comparative analysis of gene expression profiles between responding and progressive lesions.
- Bioinformatic analysis to infer tumor origin and identify resistance mechanisms.
Main Results:
- scRNA-seq identified interferon-induced APOBEC3 as a potential mechanism of acquired CPI resistance in the progressing lesion.
- Analysis suggested the progressive lesion was a metastasis rather than a new primary HNSCC.
- The study demonstrated the utility of scRNA-seq in discerning tumor origin and resistance pathways.
Conclusions:
- APOBEC3-mediated mechanisms contribute to acquired resistance against CPI in HNSCC.
- scRNA-seq is a powerful clinical tool for determining tumor metastasis and understanding therapeutic resistance.
- This approach can guide personalized treatment strategies for HNSCC patients.
