Abstract:
:T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for fas-fasL in antigen-specific T cell killing. We also found that fas-fasL mediated off-target 'bystander' killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing were reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T cell models and were augmented by inhibiting regulators of fas signaling. Tumoral FAS expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Upadhyay R,Boiarsky JA,Pantsulaia G,Svensson-Arvelund J,Lin MJ,Wroblewska A,Bhalla S,Scholler N,Bot A,Rossi JM,Sadek N,Parekh S,Laganà A,Baccarini A,Merad M,Brown BD,Brody JDdoi
10.1158/2159-8290.CD-20-0756subject
Has Abstractpub_date
2020-12-17 00:00:00eissn
2159-8274issn
2159-8290pii
2159-8290.CD-20-0756pub_type
杂志文章相关文献
Cancer Discovery文献大全abstract::53BP1 integrates pRB activity with the DNA damage response by binding to methylated K810. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2014-164
更新日期:2014-09-01 00:00:00
abstract:UNLABELLED:Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0130
更新日期:2011-11-01 00:00:00
abstract::IFNγ-producing NK cells induced TME remodeling and orchestrated T cell-mediated tumor control. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-174
更新日期:2020-12-04 00:00:00
abstract::E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0104
更新日期:2011-09-01 00:00:00
abstract::A multidisciplinary panel of experts has issued guidelines that consolidate current evidence on testing for molecular biomarkers in colorectal cancer. The guidelines aim to standardize molecular testing for patients with colorectal cancer and help clinicians identify patients most likely to benefit from targeted treat...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-030
更新日期:2017-04-01 00:00:00
abstract::The structure of CD20 with the antibody drug rituximab showed the binding mode and 2:2 stoichiometry. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-031
更新日期:2020-04-01 00:00:00
abstract::In the large international phase III MAVORIC trial, patients with previously treated cutaneous T-cell lymphoma who received the anti-CCR4 monoclonal antibody mogamulizumab experienced significantly longer progression-free survival and higher response rates, as well as better quality of life, than those who received vo...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2018-001
更新日期:2018-02-01 00:00:00
abstract::The investigational menin-MLL inhibitor KO-539 may be active in patients with acute myeloid leukemia: In a phase I trial, the agent induced complete remissions in two patients with relapsed/refractory disease and showed signs of activity in several others. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-120
更新日期:2020-12-30 00:00:00
abstract::According to survival results from a phase II trial of brentuximab vedotin, 34 patients with relapsed or refractory classic Hodgkin lymphoma had a complete response with this CD30-targeting antibody-drug conjugate; 13 remain in remission 5 years later. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2016-100
更新日期:2016-09-01 00:00:00
abstract::The FDA has approved the small-molecule inhibitor midostaurin in combination with chemotherapy to treat acute myeloid leukemia. It is the first approved drug for the disease that specifically targets FLT3 mutations, which occur in about a quarter of all AML cases and are associated with particularly poor outcomes. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-072
更新日期:2017-07-01 00:00:00
abstract::According to the final analysis of CLEOPATRA, first-line treatment with pertuzumab plus trastuzumab and docetaxel significantly improves overall survival for patients with HER2-positive metastatic breast cancer. As such, dual HER2 blockade plus chemotherapy should be the standard of care in this setting, researchers s...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2014-157
更新日期:2014-12-01 00:00:00
abstract::Loss-of-function mutations in JAK1/2 can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned that they may also be involved in primary resistance to anti-PD-1 therapy. JAK1/2-inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 pati...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-16-1223
更新日期:2017-02-01 00:00:00
abstract::The structure of the chromatin-remodeling BAF complex provides molecular-scale mechanistic insight. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2020-020
更新日期:2020-03-01 00:00:00
abstract::Spliceosome inhibitors induced mRNA missplicing, retaining introns that formed double-stranded RNA. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2021-008
更新日期:2021-01-22 00:00:00
abstract::Tumors mutated in IDH1 tend to have lower levels of the essential substrate NAD+. In this issue of Cancer Discovery, Nagashima and colleagues exploit this metabolic sensitivity by devising a combinatorial therapy that both further reduces the pools as well as sequesters the remaining substrate in PAR chains, sensitizi...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-20-1215
更新日期:2020-11-01 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-20-0133
更新日期:2020-10-01 00:00:00
abstract::With advances in technology and bioinformatics, we are now positioned to view and manage cancer through an evolutionary lens. This perspective is critical as our appreciation for the role of tumor heterogeneity, tumor immune compartment, and tumor microenvironment on cancer pathogenesis and evolution grows. Here, we e...
journal_title:Cancer discovery
pub_type: 杂志文章,评审
doi:10.1158/2159-8290.CD-18-1196
更新日期:2019-05-01 00:00:00
abstract::The Ivy Glioblastoma Atlas provides detailed information about genes expressed in different anatomic regions of human brain tumors. Researchers are already drawing upon the resource to identify novel therapeutic targets for this deadly cancer. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2018-066
更新日期:2018-07-01 00:00:00
abstract::Findings from a phase I/IIa study indicate that combining the investigational indoleamine 2,3-dioxygenase 1 inhibitor BMS-986205 with nivolumab is safe and boosts response rates among patients with bladder and cervical cancers. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-167
更新日期:2018-01-01 00:00:00
abstract::To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53, BAX, and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0125
更新日期:2019-07-01 00:00:00
abstract::Adding entinostat to exemestane improves survival in women with ER(+) advanced breast cancer. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2013-101
更新日期:2013-07-01 00:00:00
abstract::CD10 and GPR77 define a cancer-associated fibroblast (CAF) subset that sustains cancer stemness. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2018-019
更新日期:2018-03-01 00:00:00
abstract::In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechan...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-15-0616
更新日期:2015-07-01 00:00:00
abstract::The FDA approved 22 novel drugs in 2016, down from 45 in 2015. Four of the new therapies are for cancer treatment, and two are for cancer diagnosis. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-003
更新日期:2017-02-01 00:00:00
abstract::In a first-in-human trial of an anti-CD22 chimeric antigen receptor T-cell therapy in children and young adults with relapsed and refractory acute lymphocytic leukemia, researchers found that the immunotherapeutic approach was not only feasible and safe, but also effective, leading to remissions in most patients. Infu...
journal_title:Cancer discovery
pub_type:
doi:10.1158/2159-8290.CD-NB2017-001
更新日期:2017-02-01 00:00:00
abstract::Oncogenes induce premature S phase, resulting in replication-transcription conflicts and replication stress. ...
journal_title:Cancer discovery
pub_type: 评论,新闻
doi:10.1158/2159-8290.CD-RW2018-039
更新日期:2018-04-01 00:00:00
abstract::An expert panel recommended approval of Novartis's experimental chimeric antigen T-cell therapy, tisagenlecleucel, for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia. The therapy would be the first of its kind approved for cancer and has the potential to transform standard of...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-108
更新日期:2017-09-01 00:00:00
abstract::Whether metastases were seeded mono- or polyclonally depended on cancer site and treatment. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-082
更新日期:2020-07-01 00:00:00
abstract::Pancreatic ductal adenocarcinoma (PDAC) is poorly responsive to therapies and histologically contains a paucity of neoplastic cells embedded within a dense desmoplastic stroma. Within the stroma, cancer-associated fibroblasts (CAF) secrete tropic factors and extracellular matrix components, and have been implicated in...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-18-0710
更新日期:2019-02-01 00:00:00
abstract:UNLABELLED:Recent proteomic data have uncovered an interdependence of PI3K and STAT3. In PI3K-tranformed murine cells, STAT3 is phosphorylated on Y705 and activated in a PI3K-dependent manner. Dominant negative STAT3 interferes with PI3K-induced oncogenic transformation. Phosphorylation of STAT3 in PI3K-transformed mur...
journal_title:Cancer discovery
pub_type: 杂志文章,评审
doi:10.1158/2159-8290.CD-11-0218
更新日期:2011-11-01 00:00:00