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| Open AccessTargeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma
Immune checkpoint inhibitors have now been approved for the treatment of advanced hepatocellular carcinoma (HCC), however only a minority of patients appear to benefit. Here the authors report that RNase1 levels predict response to nivolumab (anti-PD1) in patients with HCC and that RNase 1 overexpression correlates with an immunosuppressive tumor microenvironment in HCC preclinical models.
- Chunxiao Liu
- , Chenhao Zhou
- & Mien-Chie Hung
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Article
| Open AccessMutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia
The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.
- Florian Märkl
- , Christoph Schultheiß
- & Mascha Binder
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Article
| Open AccessLongitudinal plasma proteome profiling reveals the diversity of biomarkers for diagnosis and cetuximab therapy response of colorectal cancer
Resistance to cetuximab is a common feature of colorectal cancer progression. Here, the authors utilize longitudinal proteomic profiling of 147 colorectal cancer patients and find potential biomarkers which can predict treatment response.
- Yan Li
- , Bing Wang
- & Chen Ding
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Article
| Open AccessNuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma
The MYC oncogene is activated in the majority of human cancers and has proven challenging to target therapeutically. In this study, the authors identify genome-wide MYC synthetic-lethal interactions that could serve as potential alternative targets for the treatment of MYC-driven cancers.
- Anja Deutzmann
- , Delaney K. Sullivan
- & Dean W. Felsher
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Article
| 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 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 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 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 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 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 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 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 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 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 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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| 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 AccessOvercoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma
The m6A reader IGF2BP3 is upregulated in various cancer, including glioblastoma. Here the authors report that IGF2BP3 facilitates NETosis and glioma survival as well as resistance to oncolytic herpes simplex virotherapy.
- Weiwei Dai
- , Ruotong Tian
- & Minfeng Shu
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Article
| Open AccessT-cell stimulating vaccines empower CD3 bispecific antibody therapy in solid tumors
CD3 bispecific antibodies (bsAbs) have demonstrated promising clinical responses in hematological malignancies but clinical benefit in solid tumors has been limited. Here the authors report that pre-treatment vaccination promotes the infiltration of tumor-(un)related effector CD8 T cells, improving the efficacy of CD3 bsAbs in solid tumors.
- Jim Middelburg
- , Marjolein Sluijter
- & Thorbald van Hall
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Article
| Open AccessMetallopolymer strategy to explore hypoxic active narrow-bandgap photosensitizers for effective cancer photodynamic therapy
Iridium-based photosensitizers exhibit good photocatalytic performance, but the in vivo applications are hindered by conventional O2-dependent Type-II photochemistry and poor absorption. Here, the authors report a general metallopolymerization strategy for engineering iridium complexes exhibiting Type-I photochemistry and enhancing absorption intensity in the blue to near-infrared region.
- Zhao Zhang
- , Zixiang Wei
- & Xuanjun Zhang
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Article
| Open AccessIL-12 reprograms CAR-expressing natural killer T cells to long-lived Th1-polarized cells with potent antitumor activity
Human natural killer T (NKT) cells have been proposed as a cellular platform for CAR engineering. Here the authors report that IL-12 engineering reprograms CAR-expressing NKT cells to long-lived Th1-polarized cells with potent anti-tumor activity in leukemia and neuroblastoma preclinical models.
- Elisa Landoni
- , Mark G. Woodcock
- & Gianpietro Dotti
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Article
| Open AccessCell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
How cell cycling coordinates with cell survival and death remains unclear. Here, the authors reveal a suppressive effect of cell cycle arrest on ferroptosis and propose a ferroptosis-inducing approach to treat slow-cycling, therapy-resistant cancers.
- Hyemin Lee
- , Amber Horbath
- & Boyi Gan
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Article
| Open AccessNeoadjuvant camrelizumab and apatinib combined with chemotherapy versus chemotherapy alone for locally advanced gastric cancer: a multicenter randomized phase 2 trial
Neoadjuvant treatment represents a therapeutic option for locally advanced gastric cancer (LAGC). Here the authors report the results of a randomized phase 2 trial of camrelizumab (anti-PD1) and apatinib (anti-VEGFR2) combined with nab-paclitaxel plus S-1 versus chemotherapy alone as neoadjuvant treatment for LAGC.
- Jian-Xian Lin
- , Yi-Hui Tang
- & Chang-Ming Huang
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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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| Open AccessNeoadjuvant durvalumab plus radiation versus durvalumab alone in stages I–III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial
The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc analysis.
- Nasser K. Altorki
- , Zachary H. Walsh
- & Timothy E. McGraw
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Article
| Open AccessPyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial
HER2 targeted therapy combined with chemotherapy represents a standard approach for treating HER2-positive metastatic breast cancer (MBC). Here the authors report the results of a phase II trial of the small molecule tyrosine kinase inhibitor pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC.
- Yabing Zheng
- , Wen-Ming Cao
- & Xiaojia Wang
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Article
| Open AccessNear-infrared light-triggered prodrug photolysis by one-step energy transfer
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions, but most of the photocleavable groups cannot be directly activated by near-infrared (NIR) light that features deep penetration and low phototoxicity. Here, the authors report an upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis.
- Kaiqi Long
- , Wen Lv
- & Weiping Wang
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Article
| Open AccessInhibiting stromal Class I HDACs curbs pancreatic cancer progression
The desmoplastic stroma constitutes part of the microenvironment in pancreatic ductal adenocarcinoma. Here the authors show that Class I HDACs regulate the pro-desmoplastic and pro-tumorigenic transcriptional programs to support stromal activation and tumour progression.
- Gaoyang Liang
- , Tae Gyu Oh
- & Ronald M. Evans
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Article
| Open AccessMetabolic tagging of extracellular vesicles and development of enhanced extracellular vesicle based cancer vaccines
Extracellular vesicles (EVs) have been actively explored for diagnostic and therapeutic applications. Here, the authors report a universal metabolic tagging technology to generate chemically tagged EVs from parent cells, modulate EV-cell interactions, and develop potent EV-based cancer vaccines.
- Rimsha Bhatta
- , Joonsu Han
- & Hua Wang
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| Open AccessLeukemia-intrinsic determinants of CAR-T response revealed by iterative in vivo genome-wide CRISPR screening
CAR-T therapy is a promising treatment modality for B-cell malignancies, yet many patients relapse. Using an in vivo genomewide screen in a model of B cell leukemia, we identify an unexpected mechanism of CAR-T resistance in which interferon gamma from the in vivo tumor microenvironment induces an adaptive T-cell resistance program in tumor cells.
- Azucena Ramos
- , Catherine E. Koch
- & Michael T. Hemann
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Article
| Open AccessStructural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8
CCR8 is a promising target in cancer immunotherapy. Here, authors generated mAb1, an antagonist antibody against CCR8 and determined structures of CCR8 in complex with mAb1 or the agonist CCL1, providing insights into CCR8 inhibition and activation.
- Dawei Sun
- , Yonglian Sun
- & Matthieu Masureel
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Article
| Open AccessThe ELAVL3/MYCN positive feedback loop provides a therapeutic target for neuroendocrine prostate cancer
Neuroendocrine prostate cancer (NEPC) is an aggressive subtype with limited effective therapeutic options. Here, the authors identify the RNA-binding protein ELAVL3 as a driver of differentiation into NEPC via a positive feedback loop with MYCN and demonstrate the use of the repurposed drug pyrvinium pamoate to target this axis using preclinical models of NEPC.
- Yiyi Ji
- , Weiwei Zhang
- & Wei Xue
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Article
| Open AccessA simeprevir-inducible molecular switch for the control of cell and gene therapies
Chemical inducer of dimerization (CID) modules can be used to effectively control biological processes; however, CID modules have been explored primarily in engineering cells for in vitro applications using inducers that have limited clinical utility. Here, the authors identify a CID module with favorable properties to enable rapid translation from in vitro applications to potential use in humans.
- Stacey E. Chin
- , Christina Schindler
- & Natalie J. Tigue
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Article
| Open AccessTamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis
Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.
- Zijian Fang
- , Giuditta Corbizi Fattori
- & Simón Méndez-Ferrer
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Article
| Open AccessLow-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells
An increasing number of preclinical and clinical studies have investigated the antitumor efficacy of combined radiotherapy and immunotherapy. Here the authors report that low-dose radiotherapy enhances the antitumor effect of dual VEGFA and PD-L1 blockade in preclinical models of hepatocellular carcinoma.
- Siqi Li
- , Kun Li
- & Yang Yang
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Article
| Open AccessMirabegron displays anticancer effects by globally browning adipose tissues
Targeting metabolism is currently a promising approach for cancer treatment. Here, the authors show that the beta3 agonist mirabegron inhibits tumor progression by browning adipose tissues in preclinical murine models.
- Xiaoting Sun
- , Wenhai Sui
- & Yihai Cao
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Article
| Open AccessCDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
TAK-931 is a selective CDC7 inhibitor and can induce replication stress (RS)-mediated chromosomal instability with antitumoral activity. Here the authors show that TAK-931-induced RS generates aneuploid cells with an inflammatory phenotype, rendering tumors sensitive to immune-checkpoint blockade.
- Tomoko Yamamori Morita
- , Jie Yu
- & Akihiro Ohashi
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Article
| Open AccessTOFIMS mass spectrometry-based immunopeptidomics refines tumor antigen identification
MS-based immunopeptidomics provides direct evidence for HLA peptide-antigen presentation, which is indispensable for therapeutic use. Here the authors present an ion mobility MS-based immunopeptidome workflow, largely expand benign reference databases and enables next generation tumor antigen discovery.
- Naomi Hoenisch Gravel
- , Annika Nelde
- & Juliane S. Walz
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Article
| Open AccessRepression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51
Here, the authors identify lysine-specific demethylase 1 is a homologous recombination (HR) regulator. Its inhibitor induces HR deficiency and sensitizes HR-proficient ovarian cancer cells to PARP inhibitors, which expand the use of PARP inhibitors.
- Lei Tao
- , Yue Zhou
- & Yinglan Zhao
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Article
| Open AccessA CRISPR-drug perturbational map for identifying compounds to combine with commonly used chemotherapeutics
Combining chemotherapeutics can be beneficial but identifying effective combinations from the vast array of possibilities is resource and time consuming. Here, the authors perform a high-throughput targeted CRISPR knock-out screen identify druggable gene targets which alter sensitivity to chemotherapies. In doing so, they identify DNA-PK inhibition as a sensitiser of neuroblastomas to doxorubicin.
- Hyeong-Min Lee
- , William C. Wright
- & Paul Geeleher
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Article
| Open AccessDostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial
Several PD-(L)1 inhibitors have been approved or are in development for the treatment of NSCLC, showing promising efficacy and tolerable safety profiles. Here, the authors present a randomized phase II clinical trial comparing two different anti-PD-1 antibodies, dostarlimab and pembrolizumab, both combined with chemotherapy as first-line treatment in patients with metastatic NSCLC.
- Sun Min Lim
- , Solange Peters
- & Filippo de Marinis
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Article
| Open AccessSphingomyelin-derived nanovesicles for the delivery of the IDO1 inhibitor epacadostat enhance metastatic and post-surgical melanoma immunotherapy
Epacadostat is a selective IDO1 inhibitor shown to promote anti-tumor immune responses in preclinical models, however it has failed in a Phase III clinical trial for treating metastatic melanoma. Here the authors design a sphingomyelin-derived nanovesicle system for epacadostat delivery with improved pharmacokinetics and anti-tumor activity when combined with a PD-1 inhibitor in melanoma preclinical models.
- Zhiren Wang
- , Wenpan Li
- & Jianqin Lu
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Article
| Open AccessDisrupting cellular memory to overcome drug resistance
Identifying memory and state switching in single cells remains elusive. Here, the authors develop a method, scMemorySeq, by combining cell barcoding and scRNA-seq and apply it to human melanoma cells to track lineages as they switch states between a drug-susceptible state and a state primed for drug resistance.
- Guillaume Harmange
- , Raúl A. Reyes Hueros
- & Sydney M. Shaffer
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Article
| Open AccessA TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation
Overexpression of human antigen R (HuR) correlates with high grade tumours and poor patient prognosis. Here, the authors engineer a TRIM21 biological PROTAC to demonstrate the benefit of a targeted protein degradation approach to deplete HuR, resulting in tumour growth inhibition in pre-clinical cancer models by altering the HuR-regulated proteome.
- Alice Fletcher
- , Dean Clift
- & James Hunt
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Article
| Open AccessDevelopment of mesothelioma-specific oncolytic immunotherapy enabled by immunopeptidomics of murine and human mesothelioma tumors
Malignant pleural mesothelioma is an aggressive cancer with a poor prognosis and limited therapeutic options. Here the authors report the immunopeptidomic landscape of murine and human mesothelioma tumors and demonstrate the anti-tumor potential of oncolytic adenoviruses coated with so-defined tumor-specific peptides in a mouse model of mesothelioma.
- Jacopo Chiaro
- , Gabriella Antignani
- & Vincenzo Cerullo
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Article
| Open AccessInhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer
A tumor cell-intrinsic hyperglycolytic state has been associated with immunosuppression and resistance to immune checkpoint blockade in triple negative breast cancer (TNBC). Here the authors describe an aptamer-based nanoassembly for tumor cell selective inhibition of glycolysis combined with bispecific immune checkpoint blockade, promoting anti-tumor immune responses in preclinical TNBC models.
- Xijiao Ren
- , Zhuo Cheng
- & Zhong Luo
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Article
| Open AccessPaclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial
Preclinical studies have shown that blockade of the CD73-adenosinergic pathway could improve anti-tumor immunity and response to other immune checkpoint inhibitors. Here the authors report the results of a randomized phase II trial of first-line durvalumab, paclitaxel and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced triple-negative breast cancer.
- Laurence Buisseret
- , Delphine Loirat
- & Martine Piccart-Gebhart
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Article
| Open AccessToxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer
Resistance to standard of care (SOC) therapies reduces survival of estrogen receptor-positive (ER+) breast cancer patients. Here the authors show that SOC therapy downregulates the ER target phosphodiesterase 4D (PDE4D), causing DNA damage and cell death upon generation of functional BRCAness, and that combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status.
- Ozge Saatci
- , Metin Cetin
- & Ozgur Sahin