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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Artículo científico |
| Language: | en |
| Published: |
Nucleic acids research
2025
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| Subjects: | |
| Online Access: | https://pubmed.ncbi.nlm.nih.gov/41273175/ |
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Table of Contents:
- Single-cell mapping of alternative splicing linked to checkpoint immunotherapy response. Xiong, Jieyi Bricard, Orian Arijs, Ingrid Demeulemeester, Jonas Gu, Chen Thienpont, Bernard Daaboul, Danie Bassez, Ayse Bechter, Oliver Poźniak, Joanna Vos, Hanne Nevelsteen, Ines Torfs, Sofie Santos, Sara Aibar Lan, Qing Hou, Yong Van Oudenhove, Lore Boons, Gitta Qian, Junbin Aerts, Stein Smeets, Ann Marine, Jean-Christophe Lambrechts, Diether Humans Single-Cell Analysis Alternative Splicing RNA-Binding Proteins Immunotherapy Tumor Microenvironment Female Immune Checkpoint Inhibitors Antigens, Neoplasm Gene Expression Regulation, Neoplastic Breast Neoplasms Cell Line, Tumor Triple Negative Breast Neoplasms Evidence suggests that alternative RNA splicing (AS) plays a critical role in tumor biology and may contribute to the generation of tumor antigens. Here, we develop a method to detect AS in short-read single-cell 5'-RNA-sequencing data, allowing us to uniquely characterize the heterogeneity and dynamic changes in AS in individual cell types within the tumor microenvironment. We identify numerous splicing events specific to either cancer cells or stromal cell types or for triple-negative versus estrogen receptor-positive breast cancers (BCs). By correlating these splice events with expression of splicing regulators in individual cells, we also identify their potential mediators. For instance, we identify and functionally validate the Epithelial Splicing Regulatory Protein-1 (ESRP1) to drive AS in BCs responding to immune checkpoint blockade (ICB). Prioritization of splicing events based on their likelihood to represent tumor antigens reveals that their aggregated load also correlates with high immune activity in multiple cancers, while also predicting expansion of T cells in BCs receiving ICB and prolonging long-term survival of cancer patients treated with ICB. Collectively, our method provides a framework for analyzing AS in single-cell data and defines a key role for AS in the response to ICB.