Deciphering the tumor immune microenvironment of imatinib-resistance in advanced gastrointestinal stromal tumors at single-cell resolution

The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients...

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Bibliographic Details
Published in:Cell death & disease 2024-03, Vol.15 (3), p.190-190, Article 190
Main Authors: Liu, Xuechao, Yu, Jing, Li, Yi, Shi, Hailei, Jiao, Xuelong, Liu, Xiaodong, Guo, Dong, Li, Zequn, Tian, Yulong, Dai, Fan, Niu, Zhaojian, Zhou, Yanbing
Format: Article
Language:English
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Antibodies
Biochemistry
Biological Evolution
Biomedical and Life Sciences
BTLA protein
Cell Biology
Cell Culture
Cytokines
Dendritic cells
Gastrointestinal cancer
Gastrointestinal Stromal Tumors - drug therapy
Gastrointestinal Stromal Tumors - genetics
Humans
Imatinib
Imatinib Mesylate - pharmacology
Imatinib Mesylate - therapeutic use
Immunofluorescence
Immunohistochemistry
Immunology
Life Sciences
Lymphocytes T
Medical innovations
Metastases
Myeloid cells
Transcriptomes
Transcriptomics
Tumor cells
Tumor Microenvironment
Tumors
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Summary:The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients diagnosed with locally advanced or advanced GIST. Single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Immunohistochemistry and multiplex immunofluorescence staining were used to further validate it. This analysis revealed unique tumor evolutionary patterns, transcriptome features, dynamic cell-state changes, and different metabolic reprogramming. The findings indicate that in imatinib-resistant TME, tumor cells with activated immune and cytokine-mediated immune responses interacted with a higher proportion of Treg cells via the TIGIT-NECTIN2 axis. Future immunotherapeutic strategies targeting Treg may provide new directions for the treatment of imatinib-resistant patients. In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-024-06571-3