Baldominos, P.; Barbera-Mourelle, A.; Barreiro, O.; Huang, Y.; Wight, A.; Cho, J.; Zhao, X.... (2022). Quiescent cancer cells resist T cell attack by forming
an immunosuppressive niche. Cell. 185(10):1694-1708. https://doi.org/10.1016/j.cell.2022.03.033
Por favor, use este identificador para citar o enlazar este ítem: http://hdl.handle.net/10251/201664
Título:
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Quiescent cancer cells resist T cell attack by forming
an immunosuppressive niche
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Autor:
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Baldominos, Pilar
Barbera-Mourelle, Alex
Barreiro, Olga
Huang, Yu
Wight, Andrew
Cho, Jae-Won
Zhao, Xi
Estivill, Guillem
Adam, Isam
Sanchez, Xavier
McCarthy, Shannon
Schaller, Julien
Khan, Zara
Ruzo, Albert
Agudo, Judith
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Fecha difusión:
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Resumen:
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[EN] Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, ...[+]
[EN] Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.
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Palabras clave:
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Tumor dormancy
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Tumor immunology
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Dendritic cells
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Cancer-associated fibroblasts
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Immunotherapy
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Breast cancer
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Tumor microenvironment
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TME
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Resistance to therapy
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T cells
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Single-cell RNA-sequencing
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Derechos de uso:
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Cerrado |
Fuente:
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DOI:
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10.1016/j.cell.2022.03.033
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Editorial:
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Elsevier
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Versión del editor:
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https://doi.org/10.1016/j.cell.2022.03.033
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Agradecimientos:
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We thank G. Freeman, K. Polyak, S.K. Dougan (DFCI), M. Haigis (HMS), C. Kim (BCH), and S. McAllister (BWH) for helpful discussions and review of the manuscript. We thank R. Weinberg (MIT) for providing 4T07 and D2A1 cells. ...[+]
We thank G. Freeman, K. Polyak, S.K. Dougan (DFCI), M. Haigis (HMS), C. Kim (BCH), and S. McAllister (BWH) for helpful discussions and review of the manuscript. We thank R. Weinberg (MIT) for providing 4T07 and D2A1 cells. We thank P.L. Sulkowski for helping us with hypoxic chamber experiments. We thank the Micron Microscopy Core (HMS) and the Molecular Imaging Core (DFCI) for image acquisition and the Brigham and Women's Hospital Single Cell Core for generation of the scRNA-seq data. P.B. was supported by La Caixa pre-doctoral fellowship (LCF/BQ/AA18/11680040) funded by ``La Caixa'' Foundation (ID 100010434). S.A.S. acknowledges support from the NCI (R50RCA211482). S.M. is funded by the T32 NIH grant (T32CA207021). A.W. is funded by the Claudia Adams Barr program for Innovative Cancer Research. J.-W.C. and M.H. were supported by the Helmsley foundation (126320) and startup funds from the Evergrande Center. J.A. was supported by the Mary Kay Foundation, the Susan G. Komen Career Catalyst award, the Smith Family Awards Program for Excellence in Biomedical Research, the Ludwig Center at Harvard, the Ira Schneider Foundation, and the DF/HCC Breast SPORE: grant 1P50CA168504. Schemes were created with BioRender.com
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Tipo:
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Artículo
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