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Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility
Metastatic uveal melanoma is poorly responsive to immune checkpoint inhibition. Here, the authors analyse 100 uveal melanoma metastases using bulk and single cell RNA-seq, TCR analysis, and immune reactivity to show potent, yet, quiescent tumour infiltrating lymphocytes that can be harnessed by adoptive transfer to confer tumour immunity.
- Shravan Leonard-Murali
- , Chetana Bhaskarla
- & Udai S. Kammula
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Article
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Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial
The feasibility and efficacy of neoadjuvant immunotherapy for resectable hepatocellular carcinoma (HCC) have been previously suggested. Here the authors report the results of a phase 1b trial of neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable HCC.
- Zhongchao Li
- , Jing Liu
- & Lei Zhao
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Article
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Enhancing NSCLC recurrence prediction with PET/CT habitat imaging, ctDNA, and integrative radiogenomics-blood insights
Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.
- Sheeba J. Sujit
- , Muhammad Aminu
- & Jia Wu
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Teacher-student collaborated multiple instance learning for pan-cancer PDL1 expression prediction from histopathology slides
PDL1 expression is a common biomarker for immunotherapy response in cancer, and it is usually quantified using immunohistochemistry. Here, the authors develop a weakly supervised learning approach combining multiple instance learning and a teacher-student framework to predict PDL1 expression from histopathological imaging.
- Darui Jin
- , Shangying Liang
- & Xiangzhi Bai
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Article
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Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms
The current stratification of Intraductal Papillary Mucinous Neoplasms (IPMN) is based on clinical and histological features rather than molecular ones. Here, the authors use spatial transcriptomics to characterise IPMN patient samples, and identify markers associated with progression to pancreatic cancer.
- Antonio Agostini
- , Geny Piro
- & Carmine Carbone
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Article
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Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Predictive role of ctDNA in esophageal squamous cell carcinoma receiving definitive chemoradiotherapy combined with toripalimab
Toripalimab with definitive chemoradiotherapy is a promising treatment strategy for esophageal squamous cell carcinoma. Here, the authors show that ctDNA positivity and bTMB are predictive of response in patients within the EC-CRT-001 phase II trial.
- Baoqing Chen
- , Shiliang Liu
- & Mian Xi
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Article
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Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Article
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Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer
‘Extrachromosomal DNA has been previously linked to tumour progression and heterogeneity, but its potential as a cancer biomarker has not been fully explored. Here, the authors develop a computational framework to refine genomic subtypes and predict response to immunotherapy in gastrointestinal cancer.
- Shixiang Wang
- , Chen-Yi Wu
- & Qi Zhao
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Article
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Regression-based Deep-Learning predicts molecular biomarkers from pathology slides
Cancer biomarkers are often continuous measurements, which poses challenges for their prediction using classification-based deep learning. Here, the authors develop a regression-based deep learning method to predict continuous biomarkers - such as the homologous repair deficiency score - from cancer histopathology images.
- Omar S. M. El Nahhas
- , Chiara M. L. Loeffler
- & Jakob Nikolas Kather
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A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
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A 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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Sequential 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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Proteomics-driven noninvasive screening of circulating serum protein panels for the early diagnosis of hepatocellular carcinoma
Hepatocellular carcinoma is often diagnosed at a late stage which limits treatment efficacy. Here, the authors utilise proteomics to identify serum proteomic biomarkers for early diagnosis, and validate using a prospective validation cohort.
- Xiaohua Xing
- , Linsheng Cai
- & Xiaolong Liu
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PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma
Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses.
- Sarah Cappuyns
- , Gino Philips
- & Jeroen Dekervel
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Molecular landscape and functional characterization of centrosome amplification in ovarian cancer
The prevalence of centrosome amplification (CA) and the genomic landscape of chromosomal instability in high-grade serous ovarian carcinoma (HGSOC) remain to be explored. Here the authors suggest CA as a potential driver of tumour evolution and a biomarker for treatment response in HGSOC.
- Carolin M. Sauer
- , James A. Hall
- & James D. Brenton
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Proteogenomics of different urothelial bladder cancer stages reveals distinct molecular features for papillary cancer and carcinoma in situ
Urothelial bladder cancer (UC) progression occurs as a multi-step process that leads to different kinds of lesions and subtypes. Here, the authors characterise benign and invasive lesions that occur during UC progression using proteogenomics in patient samples and show critical molecular pathways and prognostic associations.
- Zhenmei Yao
- , Ning Xu
- & Chen Ding
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Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype
Multiple studies have characterised the tumour microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) using single-cell RNA-seq. Here, the authors integrate the data from such single-cell studies to provide a cohesive analysis of the PDAC TME, revealing cell types and interactions that are associated with PDAC phenotypes.
- Ki Oh
- , Yun Jae Yoo
- & Richard A. Moffitt
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A qPCR technology for direct quantification of methylation in untreated DNA
Analysis of DNA methylation usually requires a chemical or an enzymatic pretreatment step. Here, the authors report a PCR-based technology for the detection of DNA methylation in untreated DNA, and present analytical and clinical results from methylation analysis of the MGMT promoter.
- Kamilla Kolding Bendixen
- , Maria Mindegaard
- & Rasmus Koefoed Petersen
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Zwitterionic microgel preservation platform for circulating tumor cells in whole blood specimen
Blood specimen stabilization for the preservation of circulating tumor cells remains challenging. Here, the authors present a zwitterionic microgel platform for long-term hypothermic preservation of circulating tumor cells in the whole blood of cancer patients for noninvasive diagnostics.
- Yiming Ma
- , Jun Zhang
- & Lei Zhang
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A multiplex blood-based assay targeting DNA methylation in PBMCs enables early detection of breast cancer
DNA methylation pattern of immune cells can be altered during tumour development. Here, the authors identify 4 DNA methylation markers in peripheral blood mononuclear cells which are predictive of breast cancer across multiple cohorts.
- Tiantian Wang
- , Peilong Li
- & Chuanxin Wang
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Article
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Circulating 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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Next generation pan-cancer blood proteome profiling using proximity extension assay
Comprehensive and scalable proteomic profiling of plasma samples can improve the screening and diagnosis of cancer patients. Here, the authors use the Olink Proximity Extension Assay technology to characterise the plasma proteomes of 1477 patients across twelve cancer types, and use machine learning to obtain a protein panel for cancer classification.
- María Bueno Álvez
- , Fredrik Edfors
- & Mathias Uhlén
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Multiplexed RNA profiling by regenerative catalysis enables blood-based subtyping of brain tumors
Current methods to subtype brain tumors rely on invasive biopsies. Here, the authors develop a digital platform to regeneratively convert and catalytically enhance signals from rare circulating RNAs for blood-based characterization of brain tumors.
- Yan Zhang
- , Chi Yan Wong
- & Huilin Shao
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Article
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Impact 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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Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma
EGFR amplification can affect temozolomide sensitivity in glioblastomas (GBM). Here the authors show that EGFR signalling mediates lysine methylation of NFAT5 which contributes to reduced efficacy of temozolomide in GBM.
- Yatian Li
- , Zhenyue Gao
- & Yu Ren
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Molecular profiling of aromatase inhibitor sensitive and resistant ER+HER2- postmenopausal breast cancers
Aromatase inhibitors are an effective treatment for ER+ breast cancer, but response is variable. Here, the authors undertake molecular analyse of response from the POETIC trial and identify several factors associated with response.
- Eugene F. Schuster
- , Elena Lopez-Knowles
- & Mitch Dowsett
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The 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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A 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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The 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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Identification 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
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PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer
Despite being an effective treatment for hepatocellular carcinoma (HCC), resistance to oxaliplatin presents a major obstacle. Here, the authors identify PRMT3-induced methylation of IGF2BP1 resulting in HEG1 stabilisation as a mechanism of oxaliplatin resistance in HCC.
- Yunxing Shi
- , Yi Niu
- & Binkui Li
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Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Epigenetic and transcriptomic characterization reveals progression markers and essential pathways in clear cell renal cell carcinoma
Tumour heterogeneity in clear cell renal cell carcinoma (ccRCC) remains to be investigated. Here, the integration of spatial omics, transcriptional and chromatin accessibility profiling at the single-nucleus level and bulk proteogenomics data reveal markers and pathways important for ccRCC.
- Yige Wu
- , Nadezhda V. Terekhanova
- & Feng Chen
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IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis
Glioblastoma stem-like cells (GSCs) contribute to therapeutic resistance and recurrence of glioblastomas. Here the authors show that Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) promotes GSCs invasion.
- Weiwei Lin
- , Rui Niu
- & Jinlong Yin
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Article
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Cellular mechanisms of heterogeneity in NF2-mutant schwannoma
Schwannomas are mainly caused by NF2 tumour suppressor inactivation, but they display intratumoural heterogeneity. Here the authors show that this heterogeneity is caused by the loss of polarity and acquisition of different programmes of ErbB ligand production in NF2-mutant Schwann cells.
- Christine Chiasson-MacKenzie
- , Jeremie Vitte
- & Andrea I. McClatchey
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Establishment and validation of a plasma oncofetal chondroitin sulfated proteoglycan for pan-cancer detection
Developing multi-cancer early detection (MCED) tests based on cfDNA or protein markers holds great promise for effective cancer screening. Here, the authors show a sensitive, non-invasive pan-cancer detection method that concurrently detects the oncofetal chondroitin sulfate (ofCS) glycans and its protein backbone in plasma.
- Pei-Fen Zhang
- , Zi-Yi Wu
- & Wei-Hua Jia
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Article
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DNA methylation analysis explores the molecular basis of plasma cell-free DNA fragmentation
Cell free DNA is produced through a non-random process. Here, the authors use orientation-aware fragmentation analysis to identify DNA methylation as a regulator of nuclease function.
- Yunyun An
- , Xin Zhao
- & Kun Sun
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Article
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CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment
The presence of classical type 1 dendritic cells (cDC1) positively influences prognosis in cancer, but their intricate networking with the various T cell types found in the tumour microenvironment is not fully appreciated. Here the authors show that cDC1 encounter with CD4+ helper T-cells transforms their gene expression signature, and these “helped” dendritic cells enable the function of anti-tumour cytotoxic T-cells.
- Xin Lei
- , Indu Khatri
- & Yanling Xiao
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Article
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Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment
Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.
- Yafei Jiang
- , Jinzeng Wang
- & Yingqi Hua
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Article
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Connecting multiple microenvironment proteomes uncovers the biology in head and neck cancer
The biological understanding of poor prognosis associated with lymph node metastasis in head and neck cancer (HNC) remains crucial. Here, a proteomic characterisation of 140 multisite samples from a 59-HNC patient cohort and machine learning reveals potential biomarkers and metastasis related signatures.
- Ariane F. Busso-Lopes
- , Leandro X. Neves
- & Adriana F. Paes Leme
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Article
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Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival
Characterisation of molecular heterogeneity in glioblastoma would improve patient stratification. Here, the authors integrate spatial proteomics and clinical data from glioblastoma patients and identify 3 molecular groups and a 5-protein signature that was associated with survival.
- Marie Duhamel
- , Lauranne Drelich
- & Michel Salzet
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Article
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Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy
Retinoblastoma response to treatment is difficult to predict. Here, the authors show that DNA methylation of cfDNA from aqueous humour is altered in retinoblastoma patients and can be used to identify the molecular subtypes and potentially predict treatment response.
- Hong-Tao Li
- , Liya Xu
- & Jesse L. Berry
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Article
| Open Access
Mutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma
Tumour mutational burden is a biomarker of immune checkpoint inhibitor response, but their association is not fully understood. Here, the authors train classifiers to identify key mutated processes which show stable predictive performance in multiple melanoma cohorts.
- Andrew Patterson
- & Noam Auslander
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Article
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Mechanistic understanding of human SLFN11
Schlafen 11 serves as an antiviral restriction factor and a predictive biomarker in cancer. Here, the authors use cryoelectron microscopy and biochemical assays to understand tRNA endoribonuclease and DNA binding functions of human Schlafen 11.
- Felix J. Metzner
- , Simon J. Wenzl
- & Katja Lammens
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Article
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The immune landscape of human thymic epithelial tumors
Thymic epithelial tumours represent a heterogenous group of malignancies with varied immune cell infiltration and prognosis. Here authors systematically analyze the phenotypes of both epithelial and immune cells that form these tumours, and identify three major subtypes with different T cell involvement that might affect prognosis.
- Zhongwei Xin
- , Mingjie Lin
- & Pin Wu
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Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Biomarkers predictive of response to T cell therapy remain to be better defined. This study identifies potential predictive and pharmacodynamic markers of response to NY-ESO-1 T-cell therapy in a solid tumor that may inform lymphodepletion, cell dose, and strategies to enhance anticancer efficacy.
- Alexandra Gyurdieva
- , Stefan Zajic
- & Ioanna Eleftheriadou
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Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics
The mutational landscape of esophageal squamous cell cancer (ESCC) remains poorly characterised. Here, the authors integrate multiple published datasets and systematically evaluate the mutational signatures and the related genomic and clinical features in ESCC.
- Minghao Li
- , Zicheng Zhang
- & Baosheng Li
A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary