Abstract:
UNLABELLED:Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiologic models of primary or metastatic disease is lacking. Investigating the impact of Ido1 gene disruption in mouse models of oncogenic KRAS-induced lung carcinoma and breast carcinoma-derived pulmonary metastasis, we have found that IDO deficiency resulted in reduced lung tumor burden and improved survival in both models. Micro-computed tomographic (CT) imaging further revealed that the density of the underlying pulmonary blood vessels was significantly reduced in Ido1-nullizygous mice. During lung tumor and metastasis outgrowth, interleukin (IL)-6 induction was greatly attenuated in conjunction with the loss of IDO. Biologically, this resulted in a consequential impairment of protumorigenic myeloid-derived suppressor cells (MDSC), as restoration of IL-6 recovered both MDSC suppressor function and metastasis susceptibility in Ido1-nullizygous mice. Together, our findings define IDO as a prototypical integrative modifier that bridges inflammation, vascularization, and immune escape to license primary and metastatic tumor outgrowth. SIGNIFICANCE:This study provides preclinical, genetic proof-of-concept that the immunoregulatory enzyme IDO contributes to autochthonous carcinoma progression and to the creation of a metastatic niche. IDO deficiency in vivo negatively impacted both vascularization and IL-6–dependent, MDSC-driven immune escape, establishing IDO as an overarching factor directing the establishment of a protumorigenic environment.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Smith C,Chang MY,Parker KH,Beury DW,DuHadaway JB,Flick HE,Boulden J,Sutanto-Ward E,Soler AP,Laury-Kleintop LD,Mandik-Nayak L,Metz R,Ostrand-Rosenberg S,Prendergast GC,Muller AJdoi
10.1158/2159-8290.CD-12-0014subject
Has Abstractpub_date
2012-08-01 00:00:00pages
722-35issue
8eissn
2159-8274issn
2159-8290pii
2159-8290.CD-12-0014journal_volume
2pub_type
杂志文章相关文献
Cancer Discovery文献大全abstract::In a phase Ib trial, a combination of the experimental immunotherapy AM0010, a PEGylated form of the recombinant human cytokine IL10, and the anti-PD-1 checkpoint inhibitor pembrolizumab was well tolerated and effective at controlling tumors in some patients with advanced renal cell carcinoma, non-small cell lung canc...
journal_title:Cancer discovery
pub_type:
doi:10.1158/2159-8290.CD-NB2016-125
更新日期:2016-12-01 00:00:00
abstract::A phase II study of the PARP inhibitor olaparib (AstraZeneca) for cancer patients with inherited BRCA1 and BRCA2 gene mutations confirmed earlier results showing clinical benefit for advanced breast and ovarian cancers, and demonstrated evidence of effectiveness against pancreatic and prostate cancers. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2013-082
更新日期:2013-07-01 00:00:00
abstract::Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identi...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0536
更新日期:2013-07-01 00:00:00
abstract::Long ignored, the importance of circadian rhythms-the focus of this year's Nobel Prize in Physiology or Medicine-is beginning to gain attention from researchers interested in cancer prevention, drug discovery, and therapeutic optimization. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-149
更新日期:2017-12-01 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::As significant increases in the costs of cancer drugs cause financial difficulties for many U.S. patients, some oncologists suggest that changes in pricing policies at the federal and state levels are inevitable. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-ND2013-018
更新日期:2013-08-01 00:00:00
abstract::Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we rep...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0710
更新日期:2020-04-01 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::Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0597
更新日期:2020-07-01 00:00:00
abstract::HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant so...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-1014
更新日期:2020-05-01 00:00:00
abstract:: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel-Lindau tumor suppressor gene (VHL), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-17-0971
更新日期:2017-11-01 00:00:00
abstract::A study shows that analyzing the protein contents of exosomes and related extracellular vesicles can distinguish tumors from nearby noncancerous tissue, and profiling extracellular vesicle proteins obtained from plasma may also reveal cancer type. The results support using vesicle proteins for liquid biopsies. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-083
更新日期:2020-11-01 00:00:00
abstract:: Farge and colleagues describe a novel in vivo approach to identify and study primary acute myeloid leukemia (AML) cells that persist in the marrow after chemotherapy. They discovered that AML cells that persist in the mouse marrow after treatment with cytarabine have increased oxidative phosphorylation and that i...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-17-0476
更新日期:2017-07-01 00:00:00
abstract::Although BRAF-MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defined. In this issue of Cancer Discovery, Erkes and colleagues present new data showing that BRAF-MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, lead...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-19-1441
更新日期:2020-02-01 00:00:00
abstract::Forty years after the signing of the National Cancer Act, we have produced a stunning repository of scientific information that is being translated into better therapies for patients. Although challenges remain, many solutions have been adopted, leading to early signs of progress against some of humankind's most dread...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0196
更新日期:2011-10-01 00:00:00
abstract::The overall budget for the NCI has increased by about $1 billion since 2009, yet the payline for new R01 grants has continued to decrease, largely due to an influx of R01 grant applications. Researchers, troubled by this trend, are wondering why the NCI is receiving so many more applications and what can be done to im...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2019-041
更新日期:2019-05-01 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:UNLABELLED:Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0124
更新日期:2011-11-01 00:00:00
abstract::In a phase III trial for patients with metastatic renal cell carcinoma, pazopanib and sunitinib offered comparable progression-free survival, but pazopanib scored higher on quality-of-life indices. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2013-131
更新日期:2014-01-01 00:00:00
abstract::Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alt...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-18-0275
更新日期:2018-09-01 00:00:00
abstract::A new report from the World Health Organization and the NCI estimates that the worldwide cost of smoking-due to health problems and lost productivity-exceeds $1 trillion annually, with the biggest economic burden falling on low- and middle- income countries. That's because proven interventions, such as tax and price i...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-014
更新日期:2017-03-01 00:00:00
abstract::The appearance of a mutant androgen receptor, AR(F876L), in prostate cancer cells chronically exposed to enzalutamide or ARN-509 promotes a switch from antagonist to agonist receptor function, undermining the potential long-term effectiveness of these second-generation antiandrogen drugs. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-13-0405
更新日期:2013-09-01 00:00:00
abstract::By law, the U.S. Food and Drug Administration has the authority, through its Center for Tobacco Products, to regulate the manufacture, marketing, and distribution of tobacco products. Its director, Mitchell Zeller, JD, talks about how the center, though its research, public education, and enforcement activities, aims ...
journal_title:Cancer discovery
pub_type: 面试
doi:10.1158/2159-8290.CD-ND2013-028
更新日期:2014-01-01 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:UNLABELLED:Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collectio...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0003
更新日期:2012-05-01 00:00:00
abstract::The clinical success of EGF receptor (EGFR) inhibitors in patients with lung cancer is limited by the inevitable development of treatment resistance. Two reports in this issue of Cancer Discovery uncover additional mechanisms by which EGFR-mutant lung cancers escape from EGFR kinase inhibitor treatment. These findings...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0387
更新日期:2012-10-01 00:00:00
abstract::Transduction of ETV2 restored blood vessel-forming capabilities to mature human endothelial cells. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-135
更新日期:2020-11-01 00:00:00
abstract::Margetuximab outperformed trastuzumab in a phase III, head-to-head trial of the two anti-HER2 agents among patients with HER2-positive metastatic breast cancer. The new antibody drug was engineered for enhanced immune activity against HER2-expressing tumor cells. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2019-069
更新日期:2019-08-01 00:00:00
abstract::Adding stereotactic ablative radiotherapy (SABR) to standard treatment slowed 6-month disease progression in men with hormone-sensitive metastatic prostate cancer, allowing them to delay androgen deprivation therapy, according to findings from the phase II ORIOLE trial. Larger studies are needed to determine if SABR, ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-034
更新日期:2020-06-01 00:00:00
abstract:UNLABELLED:Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase fami...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0504
更新日期:2013-05-01 00:00:00