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| Open AccessSafety and anti-tumour activity of the IgE antibody MOv18 in patients with advanced solid tumours expressing folate receptor-alpha: a phase I trial
IgE antibodies have shown anti-tumor activity, even superior to IgG, in preclinical models. However, all monoclonal antibodies in clinical use for cancer therapy are members of the IgG class. Here the authors report the results of a phase I clinical trial of a chimeric monoclonal IgE antibody, specific for the folate receptor-alpha, in patients with advanced solid cancer.
- James Spicer
- , Bristi Basu
- & Sophia N. Karagiannis
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Article
| Open AccessCircular RNA encoded MET variant promotes glioblastoma tumorigenesis
MET signalling is required for glioblastoma (GBM) stem cell maintenance. Here the authors identify a circular RNA from the MET gene (circMET) that encodes a MET variant protein (MET404) and show that it can promote GBM tumorigenesis by directly activating the MET receptor independent of HGF stimulation.
- Jian Zhong
- , Xujia Wu
- & Nu Zhang
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Article
| Open AccessDose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
- R. C. Coombes
- , Sacha Howell
- & Matthew G. Krebs
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Article
| Open AccessThe copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
‘Treatment resistance is common in ovarian high grade serous carcinoma, often leading to relapse. Here, the authors leverage shallow whole genome and panel sequencing of 276 patients with available diagnostic and relapse samples and show high concordance of copy number and mutation status.
- Philip Smith
- , Thomas Bradley
- & Iain A. McNeish
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Article
| Open AccessTumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
Here authors show that GDF15, a cytokine that is produced by cancer cells, prevents T cells from extravasation into the tumour microenvironment. Low availability of T cells in GDF-15-expressing tumours thus precludes effective immune therapy.
- Markus Haake
- , Beatrice Haack
- & Jörg Wischhusen
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Article
| Open AccessComputational analysis of peripheral blood smears detects disease-associated cytomorphologies
While experts analyze cytomorphology to diagnose myelodysplastic syndromes, definitive diagnosis requires complementary information such as karyotype and molecular genetics testing. Here, the authors present a computational method that automatically detects, characterizes and helps identify blood cell characteristics associated with this group of diseases.
- José Guilherme de Almeida
- , Emma Gudgin
- & Moritz Gerstung
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Article
| Open AccessCirculating trans fatty acids are associated with prostate cancer in Ghanaian and American men
Analyses of the association between fatty acids and prostate cancer have often neglected African patients. Here, the authors analyse 24 circulating fatty acids in Ghanaian, African American, and European American men, and explore the associations with socio-demographic factors, diet, FADS1/2 locus, and prostate cancer.
- Tsion Zewdu Minas
- , Brittany D. Lord
- & Stefan Ambs
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessContext-defined cancer co-dependency mapping identifies a functional interplay between PRC2 and MLL-MEN1 complex in lymphoma
Co-dependency mapping assays have revealed genetic dependencies in cancer and could shed light on chromatin crosstalk mechanisms. Here, the authors establish a pipeline to integrate co-dependency mapping screens with molecular information in pan-cancer cell lines in order to reveal chromatin complexes and potential drug targets.
- Xiao Chen
- , Yinglu Li
- & Chao Lu
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Article
| Open AccessImpact of TMB/PD-L1 expression and pneumonitis on chemoradiation and durvalumab response in stage III NSCLC
Concurrent chemoradiation and durvalumab is standard of care for stage III non-small cell lung cancer, however, efficacy is variable. Here, the authors show PD-L1 tumor proportion score expression and increased tumor mutational burden are predictive of response and that early-onset pneumonitis leading to durvalumab discontinuation is associated with poor survival.
- Joao V. Alessi
- , Biagio Ricciuti
- & Narek Shaverdian
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Article
| Open AccessMutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.
- Sujath Abbas
- , Oriol Pich
- & Maria Secrier
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Article
| Open AccessOxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers
Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models.
- Rania El-Botty
- , Ludivine Morriset
- & Elisabetta Marangoni
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Article
| Open AccessDeciphering intercellular signaling complexes by interaction-guided chemical proteomics
Systematic profiling of the indirect cell–cell interactions remains challenging. Here, the authors report a chemical proteomics method to identify ligand-receptor complexes formed between cell surface receptors and secreted proteins from neighboring cells.
- Jiangnan Zheng
- , Zhendong Zheng
- & Ruijun Tian
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Article
| Open AccessInterventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy
Minimally invasive irreversible electroporation shows some therapeutic promise in irresectable pancreatic cancers that are notorious for poor survival. Here authors combine this with administration of a hydrogel microsphere vaccine that augments the antigen presentation T cell response cascade that naturally initiates following ablation.
- Xiaoyu Liu
- , Yaping Zhuang
- & Zhongmin Wang
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Article
| Open AccessEngineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization
There are currently a lack of genetic models to study the biology of Uterine fibroids (UFs) tumours. Here the authors precisely engineer cells with mutant MED12 Gly-44 and generate myometrial smooth muscle cells (SMCs) that recapitulate major UFs-like cellular, transcriptional, and metabolic alterations.
- Kadir Buyukcelebi
- , Xintong Chen
- & Mazhar Adli
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Article
| Open AccessARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade
Loss of the E3 ubiquitin-protein ligase ARIH1 has been associated with cancer escape from anti-tumor immunity. Here the authors show that ARIH1 mediated ubiquitination and degradation of DNA-PKcs trigger activation of STING pathway in tumor cells, sensitizing tumors to immune checkpoint blockade.
- Xiaolan Liu
- , Xufeng Cen
- & Hongguang Xia
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Article
| Open AccessCancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens
YAP activation is a key driver in both malignant pleural mesothelioma and uveal melanoma through engagement of different regulatory elements. Here, the authors use functional epigenomic analyses to reveal lineage-specific YAP-dependent cistrome.
- Inês A. M. Barbosa
- , Rajaraman Gopalakrishnan
- & Giorgio G. Galli
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Article
| Open AccessThe proteomic landscape of soft tissue sarcomas
Characterising the molecular profile of soft tissue sarcomas (STS) remains critical. Here, the authors analyse samples from 321 STS patients across 11 histological subtypes using proteomics and identify prognostic signatures that can be applied to multiple subtypes.
- Jessica Burns
- , Christopher P. Wilding
- & Paul H. Huang
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Article
| Open AccessThe transcriptional landscape and diagnostic potential of long non-coding RNAs in esophageal squamous cell carcinoma
Esophageal squamous cell carcinoma is difficult to detect at early stages, and late detection is often linked to poor prognosis. Here, the authors develop a lncRNA signature predictive of ESCC and validate across multiple external cohorts.
- Meng Zhou
- , Siqi Bao
- & Zhihua Liu
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Article
| Open AccessNFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
Pancreatic acinar differentiation can be tumour suppressive for pancreatic ductal adenocarcinoma (PDAC). Here the authors identify nuclear factor I family of transcription factors NFIC as a regulator of pancreatic acinar cell function that restrains mutant KRas-driven pancreas cancer initiation in mice.
- Isidoro Cobo
- , Sumit Paliwal
- & Francisco X. Real
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Article
| Open AccessTargeting neddylation sensitizes colorectal cancer to topoisomerase I inhibitors by inactivating the DCAF13-CRL4 ubiquitin ligase complex
Repair of topoisomerase 1 (TOP1) DNA protein crosslinks (DPC) limits the efficacy of the TOP1 inhibitor irinotecan in cancer therapy. Here, the authors identify pevonedistat, NEDD8 inhibitor, as synergistic with irinotecan by blocking neddylation-activated ubiquitin/proteasomal degradation of TOP1-DPC.
- Yilun Sun
- , Simone A. Baechler
- & Yves Pommier
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Article
| Open AccessOncogenic structural aberration landscape in gastric cancer genomes
Gastric cancers (GC) are driven by genomic alterations, but the underlying molecular mechanisms remain unclear. Here, the authors analyse the structural rearrangement landscape of 170 GCs using whole-genome sequencing, identify recurrent structural variant hotspots and find oncogene amplicons driven by extrachromosomal DNA.
- Mihoko Saito-Adachi
- , Natsuko Hama
- & Tatsuhiro Shibata
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Article
| Open AccessNivolumab plus chemoradiotherapy in locally-advanced cervical cancer: the NICOL phase 1 trial
A combination of chemoradiotherapy followed by brachytherapy is recommended for patients with locally-advanced cervical cancer (LACC), however there is still a high risk of disease recurrence. Here the authors report clinical outcomes and immunologic correlates of a clinical trial of the PD-1 inhibitor nivolumab in combination with chemoradiotherapy in LACC patients.
- Manuel Rodrigues
- , Giulia Vanoni
- & Emanuela Romano
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Article
| Open AccessHypoxia induced responses are reflected in the stromal proteome of breast cancer
The role of hypoxia and metabolic reprogramming in breast cancer remains to be explored. Here, the authors investigate the landscape of secreted proteins in response to hypoxia in breast cancer cell lines and identify a stromal-based hypoxia profile in breast cancer tissue.
- Silje Kjølle
- , Kenneth Finne
- & Lars A. Akslen
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Article
| Open AccessA platform trial of neoadjuvant and adjuvant antitumor vaccination alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable pancreatic adenocarcinoma
GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.
- Thatcher Heumann
- , Carol Judkins
- & Lei Zheng
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Article
| Open AccessATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion
The ATR kinase has essential functions apart from its role in DNA replication stress. Here the authors find that in mouse primary B cells ATR tempers the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
- Demis Menolfi
- , Brian J. Lee
- & Shan Zha
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Article
| Open AccessSingle cell profiling of female breast fibroadenoma reveals distinct epithelial cell compositions and therapeutic targets
Fibroadenoma occurrence is linked to increased long-term risk of breast carcinoma, however, the lack of models has made understanding this mechanism unclear. Here, the authors use single cell RNA-seq to identify dysregulation of epithelial cells and develop organoid models to study treatment resistance.
- Zhigang Chen
- , Yi Zhang
- & Jian Huang
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| Open AccessPhase 1b trial of anti-EGFR antibody JMT101 and Osimertinib in EGFR exon 20 insertion-positive non-small-cell lung cancer
Patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions are resistant to early generation EGFR tyrosine kinase inhibitors (TKI). Here, the authors report the safety and preliminary efficacy of a phase I clinical trial JMT101, an anti-EGFR antibody, combined with EGFR-TKI, afatinib or osimertinib, in patients with NSCLC.
- Shen Zhao
- , Wu Zhuang
- & Wenfeng Fang
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Article
| Open AccessA pilot study of lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell therapy in patients with advanced solid tumors
The majority of adoptive T cell therapy-based clinical studies are based on the ex vivo expansion of neoantigen-specific tumor infiltrating lymphocytes. Here the authors report the results of a pilot study of adoptive cell therapy with personalized neoantigen-specific CD8 + T cells obtained from peripheral blood mononuclear cells in patients with locally advanced or metastatic solid tumors refractory.
- Dandan Li
- , Chao Chen
- & Rui-Hua Xu
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Article
| Open AccessNeutralizing IFNγ improves safety without compromising efficacy of CAR-T cell therapy in B-cell malignancies
B cell malignancies resistant to conventional treatments are potentially sensitive to CAR-T cell immune therapy, but its clinical applicability is limited by immune related adverse effects. Here authors show in a humanized mouse model that blocking IFNγ with the monoclonal antibody emapalumab mitigates the adverse effects of CAR.CD19-T cells without compromising their anti-lymphoma efficacy.
- Simona Manni
- , Francesca Del Bufalo
- & Concetta Quintarelli
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Article
| Open AccessALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma
Chimeric antigen receptor T (CAR-T) cells represent a breakthrough in the treatment of haematopoietic malignancies, however, in solid tumours this form of immune therapy is hampered by the scarcity of suitable targets showing high level tumour-restricted expression. Here authors generate CAR-T cells that target an osteosarcoma-specific isoform of alkaline phosphatase and show efficacy in orthotopic animal models while sparing healthy tissues.
- Nadia Mensali
- , Hakan Köksal
- & Sébastien Wälchli
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| Open AccessIdentification of BRCA1/2 mutation female carriers using circulating microRNA profiles
BRCA1/2 mutations are known to increase risk of breast and ovarian cancer but carrier status in healthy individuals is unknown without genetic testing. Here, the authors created a circulating miRNA signature to predict BRCA1/2 carrier status in healthy individuals to aid the decision process on genetic testing.
- Kevin Elias
- , Urszula Smyczynska
- & Dipanjan Chowdhury
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Article
| Open AccessA high-throughput test enables specific detection of hepatocellular carcinoma
DNA methylation analysis is a promising method to detect liver cancer. Here, the authors develop a 5 CpG site signature which can detect HCC at high specificity across multiple cohorts.
- David Cheishvili
- , Chifat Wong
- & Mamun Al Mahtab
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| Open AccessDrug screening at single-organoid resolution via bioprinting and interferometry
Traditional 2D cell culture platforms do not accurately reflect the physiology of human tumors. Here, authors combine bioprinting and high-speed live cell interferometry with machine learning to measure drug sensitivity at single-organoid resolution in a label-free manner.
- Peyton J. Tebon
- , Bowen Wang
- & Alice Soragni
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Article
| Open AccessLysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Lysophosphatidic acid is known to increase in concentration in multiple cancer types. Here, the authors show it affects CD8 T cell metabolism, phenotype, and effector functions, and plasma concentrations appear predictive of response to immunotherapy.
- Jacqueline A. Turner
- , Malia A. Fredrickson
- & Raul M. Torres
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Article
| Open AccessNOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1
Patients with lung adenocarcinoma (LUAD) patients carrying EGFR mutations are often treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but sensitivity to the therapy varies. Here, using 3D printed patient derived xenograft models, the authors identify a NOTCH mutation as an indicator of favourable response to EGFR-TKI in LUAD.
- Bin Zhang
- , Shaowei Dong
- & Chang Zou
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Article
| Open AccessThe blood proteome of imminent lung cancer diagnosis
Lung cancer screening could enhance early diagnosis and treatment. Here, the authors used proteomic analysis of pre-diagnosis samples across 6 cohorts to identify 36 proteins associated with imminent lung cancer diagnosis.
- Demetrius Albanes
- , Karine Alcala
- & Wei Zheng
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Article
| Open AccessLeukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation
Graft-versus-leukemia reactions are required for the eradication of myeloid malignancies after allogeneic hematopoietic cell transplantation. However, treatment efficacy is variable, depending on the immunological response. Here the authors show that dysfunction of HLA heterogeneity is associated with post-transplant leukemia relapse.
- Simona Pagliuca
- , Carmelo Gurnari
- & Jaroslaw P. Maciejewski
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Article
| Open AccessIdentification of fatty acid amide hydrolase as a metastasis suppressor in breast cancer
Long-term metastatic relapse is observed in patients with luminal breast cancer (BC). Here, the authors show that fatty acid amide hydrolase is a tumour suppressor for lung metastasis in mouse models of BC and a predictor of metastasis in patients with luminal BC.
- Isabel Tundidor
- , Marta Seijo-Vila
- & Eduardo Pérez-Gómez
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Article
| Open AccessLysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase
Novel strategies are needed to overcome chemotherapy resistance. Here the authors report chemotherapy induces the phosphorylation of Lysyl oxidase-like 3, which in turn stabilizes dihydroorotate dehydrogenase (DHODH) and that DHODH inhibitor sensitizes tumor cells to oxaliplatin treatment by inducing ferroptosis in liver cancer.
- Meixiao Zhan
- , Yufeng Ding
- & Xiongjun Wang
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| Open AccessTowards evidence-based response criteria for cancer immunotherapy
Early detection of immunotherapy-induced tumor response is of major benefit for patients but can be complicated by therapy-induced pseudoprogression. A consensus guideline-iRECIST- was developed as a modification of Response Evaluation Criteria in Solid Tumours (RECIST version 1.1). Here we describe which next steps are required to test its validity and how novel approaches for response criteria might be developed and included.
- Elena Garralda
- , Scott A. Laurie
- & Elisabeth G. E. de Vries
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Article
| Open AccessSingle-cell analysis of gastric signet ring cell carcinoma reveals cytological and immune microenvironment features
The tumour microenvironment in signet ring cell carcinoma (SRCC) remains to be characterised. Here, the authors perform single-cell RNA sequencing and reveal distinct features compared to moderately/poorly differentiated adenocarcinoma.
- Weizhu Zhao
- , Yanfei Jia
- & Jie Chai
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Article
| Open AccessDurvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin
Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin.
- J. Capdevila
- , J. Hernando
- & J. L. Manzano
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Article
| Open AccessMicrobial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy
Prussian blue has been used as a photothermal agent for cancer therapy. Here the authors describe the production of Prussian blue nanoparticles from S. oneidensis MR-1 bacteria and show that a Prussian blue-based mitochondria-targeting nanoplatform potentiates response to immune checkpoint blockade.
- Dongdong Wang
- , Jiawei Liu
- & Yanli Zhao
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Article
| Open AccessDasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Despite playing a central role the treatment of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), resistance to glucocorticoids remains a major obstacle. Here, the authors identify activation of PI3K/mTOR and CREB pathways as a driver of GC-resistance in BCP-ALL and restore sensitivity using the multi kinase inhibitor, dasatinib.
- Jolanda Sarno
- , Pablo Domizi
- & Kara L. Davis
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Article
| Open AccessAlanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss
Cancers with concomitant SMARCA4/2 deficiencies are often resistant to chemotherapies and confer a poor prognosis. Here, the authors identify a metabolic dependency of these tumours on glutamine as an energy source and, using multiple approaches, demonstrate the efficacy of therapeutically targeting this vulnerability.
- Xianbing Zhu
- , Zheng Fu
- & Sidong Huang
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Article
| Open AccessADAR1-mediated RNA editing of SCD1 drives drug resistance and self-renewal in gastric cancer
Resistance to 5-fluorouracil and cisplatin (5FU + CDDP) presents a major issue in patients with gastric cancer. Here, the authors establish 5FU + CDDP resistant intestinal gastric cancer patient-derived organoids and identify JAK/STAT-ADAR1 altered lipid metabolism as a regulator of chemoresistance.
- Tin-Lok Wong
- , Jia-Jian Loh
- & Stephanie Ma
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Article
| Open AccessERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
Ubiquitination and deubiquitination processes regulate the stability of PD-1, affecting T cell biology. Here the authors identify the ubiquitin-specific protease 5 (USP5) as a deubiquitinase for PD-1 and show that USP5 inhibition in combination with a MEK inhibitor or anti-CTLA-4 could promote anti-tumor immune responses in preclinical models.
- Xiangling Xiao
- , Jie Shi
- & Jinfang Zhang
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Article
| Open AccessClinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma
Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.
- Darren Wan-Teck Lim
- , Hsiang-Fong Kao
- & N. Gopalakrishna Iyer