A major chromatin regulator determines resistance of tumor cells to T cell–mediated killing
By D. Pan, Aya Kobayashi, Peng Jiang, L. F. Andrade, R. Tay, Adrienne M. Luoma, Daphne M Tsoucas, X. Qiu, Klothilda Lim, Prakash K. Rao and 6 more. Science, 2018
746 citations recorded by the source corpus.
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 Inactivation of a chromatin remodeling complex in tumor cells enhances their sensitivity to killing by T cells. Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes—including Pbrm1, Arid2, and Brd7, which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex—sensitized mouse B16F10 melanoma cells to killing by T cells. Loss of PBAF function increased tumor cell sensitivity to interferon-γ, resulting in enhanced secretion of chemokines that recruit effector T cells. Treatment-resistant tumors became responsive to immunotherapy when Pbrm1 was inactivated. In many human cancers, expression of PBRM1 and ARID2 inversely correlated with expression of T cell cytotoxicity genes, and Pbrm1-deficient murine melanomas were more strongly infiltrated by cytotoxic T cells.
Subfields: Molecular Biology, Oncology, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/8cf8ed7c7e0aead794fd381a529c573095b54bb4
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
In Oncology
Citations in the corpus
- Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “The Polybromo-associated BAF (PBAF) SWI/SNF complexes were found to be a positive regulator of MHC I expression (198).”
- Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “, which also found Ptpn2 and IFNγ signaling was enriched in ICI resistance, reveals critical components of the SWI/SNF chromatin remodeling complex can suppress IFNγ signaling and thereby mediate T cell antitumor immunity (Pan et al., 2018).”