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| Open AccessToripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial
Although most patients achieve complete response after standard-of-care treatment, residual disease in patients with nasopharyngeal carcinoma is associated with poor prognosis. Here the authors report the results of a phase 2 trial of toripalimab (anti-PD1) plus capecitabine for patients with residual nasopharyngeal carcinoma.
- Xun Cao
- , Hao-Yang Huang
- & Xing Lv
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Article
| Open AccessBacterial protoplast-derived nanovesicles carrying CRISPR-Cas9 tools re-educate tumor-associated macrophages for enhanced cancer immunotherapy
CRISPR-Cas9 genome editing systems have great potential in cancer therapy. Here the authors report a gene-editing delivery system using functionalized nanovesicles derived from E. coli protoplasts to encapsulate Cas9-sgRNA ribonucleoprotein for the selective targeting of Pik3cg in tumor associated macrophages.
- Mingming Zhao
- , Xiaohui Cheng
- & Junfeng Zhang
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Article
| Open AccessFLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress
Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.
- Jessica D. Tischler
- , Hiroshi Tsuchida
- & Richard O. Adeyemi
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Article
| Open AccessIn-situ-sprayed therapeutic hydrogel for oxygen-actuated Janus regulation of postsurgical tumor recurrence/metastasis and wound healing
Surgery is a primary therapeutic modality for treating melanoma, but it is challenging to tackle tumor recurrence/metastasis and postsurgical wounds. Here the authors report a sprayable hydrogel capable of long-lasting and controllable oxygen supply for preventing tumor recurrence/metastasis and simultaneously promoting wound healing during the postsurgical treatment of melanoma.
- Shuiling Chen
- , Yang Luo
- & Shaobing Zhou
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Article
| Open AccessCaloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.
- Rani Pallavi
- , Elena Gatti
- & Pier Giuseppe Pelicci
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Article
| Open AccessReconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset
The cellular origin of human pancreatic ductal adenocarcinoma (PDAC) is still unclear. Here the authors used human primary acinar and ductal cells to successfully reconstitute PDAC tumorigenesis from both lineages and revealed transcriptional changes during early PDAC progression.
- Yi Xu
- , Michael H. Nipper
- & Pei Wang
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Article
| Open AccessNon-invasive transdermal delivery of biomacromolecules with fluorocarbon-modified chitosan for melanoma immunotherapy and viral vaccines
Different approaches have been described for the transdermal delivery of drugs. Here the authors report the design of a fluorocarbon modified chitosan-based non-invasive transdermal platform for the delivery of biomacromolecules, such as viral antigens for vaccines or immune checkpoint inhibitors for melanoma immunotherapy.
- Wenjun Zhu
- , Ting Wei
- & Zhuang Liu
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Article
| Open AccessA wearable electrostimulation-augmented ionic-gel photothermal patch doped with MXene for skin tumor treatment
A wearable biological patch capable of producing multiple responses to light and electricity without interfering with daily activities is desired for skin cancer treatment but remains elusive. Herein, the authors report a skin-mountable and dual-responsive electrothermal patch for melanoma treatment by the co-therapy of photothermal and electrical stimulations.
- Xingkai Ju
- , Jiao Kong
- & Yongdong Jin
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Article
| Open AccessTransposable elements mediate genetic effects altering the expression of nearby genes in colorectal cancer
It has been suggested that transposable elements (TE) play a role in tumourigenesis, but the associated mechanisms remain unclear. Here, the authors show, using colorectal cancer data and Bayesian Networks, that TEs can mediate the effect of expression quantitative trait loci and contribute to the regulation of cancer-related genes.
- Nikolaos M. R. Lykoskoufis
- , Evarist Planet
- & Emmanouil T. Dermitzakis
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Article
| Open AccessMHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides
Defective immune responses have been reported in cutaneous T-cell lymphoma (CTCL). Here the authors show that in patients with mycosis fungoides, the most common CTCL, malignant T cells upregulate MHC-I as a mechanism to evade NK-mediated immunity.
- Yun-Tsan Chang
- , Pacôme Prompsy
- & Emmanuella Guenova
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Article
| Open AccessInterplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas
ATRX inactivation occurs often in IDH-mutant gliomas and has been associated with immune dysfunction. Here, using preclinical models of glioma, the authors show that ATRX inactivation promotes innate immune signalling in response to double stranded RNA-based innate immune agonists, an effect that is masked in IDH-mutant tumours, presenting a therapeutic vulnerability.
- Seethalakshmi Hariharan
- , Benjamin T. Whitfield
- & David M. Ashley
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Article
| Open AccessRobustly federated learning model for identifying high-risk patients with postoperative gastric cancer recurrence
Medical data faces isolation and cross-center performance issues. Here, the authors propose a robust federated learning model to identify high-risk postoperative gastric cancer recurrence, achieving promising results across data from four independent medical institutions.
- Bao Feng
- , Jiangfeng Shi
- & Wansheng Long
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Article
| Open AccessRapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.
- Isaac Dean
- , Colin Y. C. Lee
- & David R. Withers
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Article
| Open AccessTumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity
Recognition of tumour antigen induces dendritic cell activation and migration to the lymph node. Here, the authors use photoconvertible mice to demonstrate that some activated dendritic cells are retained in tumours and gradually lose function, but their ability to support local anti-tumour responses can be augmented by anti-PD-L1 blockade.
- Colin Y. C. Lee
- , Bethany C. Kennedy
- & Menna R. Clatworthy
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Article
| Open AccessAKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
The metabolic switch of tumours to aerobic glycolysis can allow them to meet their increasing energetic demands. Here, the authors show that AKT1 regulates this switch through the phosphorylation of malic enzyme 2 (ME2) preventing mitochondrial translocation. In turn this pushes the cell from mitochondrial metabolism to glycolysis, promoting tumour growth.
- Taiqi Chen
- , Siyi Xie
- & Wenjing Du
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Article
| Open AccessDurvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial
Response rates to immune-checkpoint inhibitors in patients with advanced sarcoma remain modest. Here the authors report the results of a phase 2 study of durvalumab (anti-PD-L1) in combination with the anti-VEGF receptor tyrosine-kinase inhibitor pazopanib in unselected advanced sarcomas with correlative genomic analysis.
- Hee Jin Cho
- , Kum-Hee Yun
- & Hyo Song Kim
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Article
| Open AccessActivating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease
The inability of tyrosine kinase inhibitors to eliminate quiescent leukaemic stem cells (LSC) in chromic myeloid leukaemia (CML) results in recurrence. Here, the authors identify a reliance of CML LSCs on low P53 expression for self-renewal and therapeutically target this by combining an MDM2 inhibitor with TKI in preclinical models of CML.
- Mary T. Scott
- , Wei Liu
- & David Vetrie
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Article
| Open AccessA telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer
Therapeutic options for small cell lung cancer (SCLC) are limited. Here the authors show that a telomere-targeting drug, 6-Thio-2’-deoxyguanosine, inhibits growth of SCLC tumors by inducing telomere dysfunction preferentially in cancer initiating cells and promoting anti-tumor immune responses.
- Buse Eglenen-Polat
- , Ryan R. Kowash
- & Esra A. Akbay
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Article
| Open AccessMARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer
Detection of neoepitopes from tumours is time consuming and requires the integration of genomic and/or RNA sequencing expression data. Here, the authors propose a machine learning method to enable direct identification of additional, tumour-specific sequences using mass spectrometry through integration of de novo peptide sequencing scores, MHC class I binding prediction, and peptide retention time prediction.
- Hanqing Liao
- , Carolina Barra
- & Nicola Ternette
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Article
| Open AccessCell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
It has been reported that the circadian clock regulator Bmal1 can modulate tumorigenesis. Here the authors show that ectopic expression of Bmal1 promotes an immune resistant mesenchymal melanoma cell state associated with increased AP-1 activity.
- Xue Zhang
- , Shishir M. Pant
- & Chi V. Dang
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Article
| Open AccessLeukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Cancer cachexia is a systemic syndrome characterized by dramatic weight loss and decline in adipose tissue and skeletal muscle mass. Here, the authors show that overexpression of leukemia inhibitory factor (LIF), a secreted cytokine, suppresses de novo lipogenesis and induces cachexia in mice.
- Xue Yang
- , Jianming Wang
- & Wenwei Hu
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Article
| Open AccessMacro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- , Lei-Lei Wu
- & Jia Fan
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Article
| Open AccessEngineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.
- Candice R. Gurbatri
- , Georgette A. Radford
- & Tal Danino
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Article
| Open AccessBispecific BCMA/CD24 CAR-T cells control multiple myeloma growth
BCMA-specific CAR T-cell therapies have shown high response rates in multiple myeloma (MM), however the majority of patients still relapse. Here the authors show that CD24-positive MM cells increase after BCMA-CAR-T treatment in patients, and that dual-targeted BCMA/CD24 CAR-T cells can improve anti-tumor efficacy in MM preclinical models.
- Fumou Sun
- , Yan Cheng
- & Fenghuang Zhan
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Article
| Open AccessThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open AccessClinical application of tumour-in-normal contamination assessment from whole genome sequencing
Assessing tumour contamination in normal samples is critical for accurate variant calling in cancer samples. Here, the authors develop TINC, a computational method to determine the level of tumour in normal contamination, and demonstrate its application in the Genomics England 100,000 Genomes Project dataset.
- Jonathan Mitchell
- , Salvatore Milite
- & Giulio Caravagna
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Article
| Open AccessGeneration and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Clonal Vb2 usage is common among patients with mature T cell lymphoma. Here the authors report the generation of allogeneic CAR-T cells selectively targeting TCR Vb2+ on malignant T cells, with limited normal T cell destruction.
- Jingjing Ren
- , Xiaofeng Liao
- & Michael Girardi
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Article
| Open AccessFunctional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance
The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.
- Harish N. Vasudevan
- , Emily Payne
- & David R. Raleigh
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Article
| Open AccessEpigenetic reprogramming shapes the cellular landscape of schwannoma
Schwannomas are regularly treated with radiotherapy, but the molecular effects on these tumours and their microenvironment remain unclear. Here, the authors show that radiotherapy can induce epigenetic reprogramming and immune infiltration in schwannomas, and develop the snARC-seq approach to analyse the epigenomic evolution at the single-cell level.
- S. John Liu
- , Tim Casey-Clyde
- & David R. Raleigh
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Article
| Open AccessCarcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial
Oncolytic measles virus (MV) vaccine strains have shown preclinical antitumor activity against glioblastoma (GBM). Here the authors report the results of a phase 1 trial of intratumoral administration of a MV strain engineered to express the carcinoembryonic antigen in patients with recurrent GBM including assessment of viral replication and proinflammatory remodeling of the treated tumors.
- Evanthia Galanis
- , Katharine E. Dooley
- & Ian F. Parney
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Article
| Open AccessMutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death
Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”
- Chi Zhou
- , Wenxin Li
- & Huashan Liu
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Article
| Open AccessSingle-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state
Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype.
- Thomas F. Barrett
- , Bhuvic Patel
- & Albert H. Kim
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Article
| Open AccessDesign-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.
- Arun Chandramohan
- , Hubert Josien
- & Anthony W. Partridge
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Article
| Open AccessA transcriptome based molecular classification scheme for cholangiocarcinoma and subtype-derived prognostic biomarker
Cholangiocarcinoma can arise anywhere within the biliary tree and is classified by anatomical locations. Here, the authors utilised RNAseq from 438 CCA patients and propose a molecular classification system independent of location.
- Zhongqi Fan
- , Xinchen Zou
- & Guoyue Lv
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Article
| Open AccessThe HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.
- Gail D. Lewis
- , Guangmin Li
- & Eunpi Cho
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Article
| Open AccessIn vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy
The poor tumour delivery efficacy of GPX4 inhibitor has dampened its in vivo therapeutic value. Here the authors report a peptide ferriporphyrin conjugate to improve tumour penetration, endocytosis and GPX4 inhibition, synergistically enhancing its anticancer activity by ferroptosis.
- Da-Yong Hou
- , Dong-Bing Cheng
- & Hao Wang
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Article
| Open AccessEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Article
| Open AccessTFEB drives mTORC1 hyperactivation and kidney disease in Tuberous Sclerosis Complex
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs. Here, the authors show that TFEB is the primary driver of renal disease and mTORC1 hyperactivation in TSC.
- Nicola Alesi
- , Damir Khabibullin
- & Elizabeth P. Henske
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Article
| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
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Article
| Open AccessMechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC
Heterogeneous response to Enzalutamide remains a critical issue in castration-resistant prostate cancer (CRPC). Here, the authors reconstruct a CRPC-specific mechanism-centric regulatory network to identify signatures of Enzalutamide response and predict patients at risk of Enzalutamide resistance.
- Sukanya Panja
- , Mihai Ioan Truica
- & Antonina Mitrofanova
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Article
| Open AccessDevelopmental basis of SHH medulloblastoma heterogeneity
The role of developmental pathways in medulloblastoma tumours (MB) with sonic hedgehog (SHH) activation remains to be explored. Here, the authors perform multi-omic analysis and characterise the key transcriptomic and metabolic patterns of highly differentiated cells in SHH MBs.
- Maxwell P. Gold
- , Winnie Ong
- & Ernest Fraenkel
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Article
| Open AccessDistinct mesenchymal cell states mediate prostate cancer progression
The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- , Mohamed Omar
- & Massimo Loda
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Article
| Open AccessNeutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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Article
| Open AccessTET2-mediated tumor cGAS triggers endothelial STING activation to regulate vasculature remodeling and anti-tumor immunity in liver cancer
Activation of the cGAS-STING pathway has been associated with the promotion of anti-tumor immunity. Here the authors show that TET2 upregulates tumor cGAS to activate STING in endothelial cells, inducing tumor vascular normalization and enhancing efficacy of anti-PD-L1 alone or combined with IL-2 in liver cancer preclinical models.
- Hongwei Lv
- , Qianni Zong
- & Wen Yang
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Article
| Open AccessInhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy
A pro-tumorigenic role of iRhom1 has been described in several cancer types. Here the authors show that iRhom1 regulates sensitivity to chemotherapy and immune response, as well they report that CD44 targeting nanoparticle-mediated co-delivery of iRhom1 pre-siRNA promotes anti-tumor immune responses in preclinical cancer models.
- Zhangyi Luo
- , Yixian Huang
- & Song Li
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Article
| Open AccessTargeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open AccessSequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial
SECOMBIT was a clinical trial testing different sequences of immunotherapy (ipilimumab plus nivolumab) and targeted therapy (encorafenib plus binimetinib) for untreated BRAF-mutated metastatic melanoma. Here the authors report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy, and preliminary biomarkers evaluation.
- Paolo A. Ascierto
- , Milena Casula
- & Giuseppe Palmieri
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Article
| Open AccessPharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.
- Wenfeng Ren
- , Zilong Xu
- & Ningshao Xia
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Article
| Open AccessBipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial
Bipolar androgen therapy (BAT) is a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Here the authors report the results of a phase 2 trial of BAT plus nivolumab (anti-PD1) in patients with advanced mCRPC.
- Mark C. Markowski
- , Mary-Ellen Taplin
- & Emmanuel S. Antonarakis
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