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A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing
Open accessAbstract
SNF'ing out antitumor immunity: Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745
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“Pooled in vivo and in vitro CRISPR-Cas9 based screening have nominated several tumour intrinsic drivers of resistance to immunotherapy 4,8-11 , but therapeutic applications of these findings remain limited.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [10]
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“thus it is surprising that TBK1 has been nominated as a candidate immune evasion gene 4,9-11”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [10]
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“CRISPR/Cas9 KO screens in murine models or engineered human cell lines testing tumor-T cell interactions identified putative novel mechanisms of immune evasion involving chromatin regulators10, TNFα signaling11, SOX412, PTPN213, and APLNR10, yet their clinical relevance is unclear.”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [12]
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“consistent with prior reports12, induction of CD49f, which encodes an integrin associated with epithelial-to-mesenchymal transition (EMT).”
From Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion (2021) · cites this paper as [12]
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“In previous screens, antigen-specific T cells targeting model tumor associated antigen (TAA), such as OVA, gp100, and NY-ESO-1, were used (Manguso et al., 2017; Pan et al., 2018; Patel et al., 2017).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Pan et al., 2018
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“Several studies have demonstrated that mutations in genes involved in the SWI-SNF chromatin remodeling complex may sensitize human tumors to ICIs and that treatment with an epigenetic modulator can potentiate the ICI-mediated antitumor response through increased production of chemokines responsible for recruiting CD8 + T cells (104-107).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [105]
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Metadata
- Authors
- Pan, D., Kobayashi, A., Jiang, P., Ferrari de Andrade, L., Tay, R. E., Luoma, A. M., Tsoucas, D., Qiu, X., Lim, K., Rao, P., Long, H. W., Yuan, G.-C., Doench, J., Brown, M., Liu, X. S., & Wucherpfennig, K. W.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Astellas Pharma (Japan) (JP)
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Pan, Deng
- Kobayashi, Aya
- Jiang, Peng
- Liu, X. Shirley
- Wucherpfennig, Kai W.
- ORCID
- Venue
- Science
- Published
- 2018-02-16
- Volume
- 359
- Issue
- 6377
- Pages
- 770-775
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5953516
- OpenAlex
- W2782124401
- Cited by
- 852
- References
- 51
- Citations by year
- 2026: 39 · 2025: 96 · 2024: 92 · 2023: 107 · 2022: 123 · 2021: 117 · 2020: 143 · 2019: 86 · 2018: 47
- FWCI
- 36.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA173750)
- Astellas Pharma
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- SWI/SNF complex, PBRM1, immune checkpoint inhibitors, T cell-mediated killing, antitumor immunity, interferon-gamma, renal cell carcinoma, chromatin regulation
- MeSH terms
- CRISPR-Associated Protein 9, Bromodomain Containing Proteins, Animals, Bacterial Proteins, Chromosomal Proteins, Non-Histone, Cytotoxicity, Immunologic, DNA-Binding Proteins, Endonucleases, Genetic Testing, Humans, Immunotherapy, Interferon-gamma, Melanoma, Experimental, Skin Neoplasms, T-Lymphocytes, Cytotoxic, Transcription Factors, HMGB Proteins, Cell Line, Tumor, Mice, CRISPR-Cas Systems
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