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| Open AccessUncertainty-informed deep learning models enable high-confidence predictions for digital histopathology
Safe clinical deployment of deep learning models for digital pathology requires reliable estimates of predictive uncertainty. Here the authors describe an algorithm for quantifying whole-slide image uncertainty, demonstrating their approach with models trained to distinguish lung cancer subtypes.
- James M. Dolezal
- , Andrew Srisuwananukorn
- & Alexander T. Pearson
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| Open AccessRemodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer
AXL is overexpressed and has been investigated as a therapeutic target in several cancer types, including lung cancer. Here the authors design AXLdirected CAR-T cells and show that their anti-tumor activity can be improved in combination with microwave ablation in preclinical lung cancer models.
- Bihui Cao
- , Manting Liu
- & Zhenfeng Zhang
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Article
| Open AccessPhase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas
Generation of TNF-α in response to chemotherapy has been associated with chemo-resistance and metastasis propagation. Here the authors show that the combination of an anti-TNF antibody and cisplatin doublet chemotherapy increases anti-tumor efficacy in lung cancer preclinical models and report the results of a phase I clinical trial of the anti-TNF-α antibody certolizumab in combination with chemotherapy in patients with stage IV lung adenocarcinomas.
- Paul K. Paik
- , Jia Luo
- & Mark G. Kris
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Article
| Open AccessFibrocytes boost tumor-supportive phenotypic switches in the lung cancer niche via the endothelin system
Fibrocytes are monocyte-derived cells implicated in wound healing. Here, the authors utilise single cell RNA-seq, genetic ablation and multiplexed imaging to identify a fibrocyte population in lung cancer models, and use human lung cancer coculture systems to highlight their potential to modulate microenvironmental niche and sensitivity to endothelin blockade.
- Andreas Weigert
- , Xiang Zheng
- & Rajkumar Savai
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Article
| Open AccessThe spatial transcriptomic landscape of non-small cell lung cancer brain metastasis
Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) are associated with dismal outcomes, and are possibly sustained by the brain microenvironment. Here, the authors analyse NSCLC BrMs using Digital Spatial Profiling and reveal fibrosis, immune suppression, and cell reprogramming in the BrM microenvironment.
- Qi Zhang
- , Rober Abdo
- & Shawn Shun-Cheng Li
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Article
| Open AccessZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer
Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance.
- Chen Ni
- , Xiaohan Lou
- & Zhihai Qin
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Article
| Open AccessRAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma
Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.
- Philip East
- , Gavin P. Kelly
- & Sophie de Carné Trécesson
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Article
| Open AccessGenomic and biological study of fusion genes as resistance mechanisms to EGFR inhibitors
Fusion genes have been proposed as a potential mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Here, the authors identify gene fusions that are associated with resistance to EGFR TKIs in non-small cell lung cancers, and test how these fusions impact the response to EGFR TKIs in vitro.
- Yoshihisa Kobayashi
- , Geoffrey R. Oxnard
- & Pasi A. Jänne
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Article
| Open AccessRegulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1
LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.
- Hsiao-Yun Chen
- , Yavuz T. Durmaz
- & Matthew G. Oser
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Article
| Open AccessBlocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Cancer-associated cachexia is characterized by loss of body weight, skeletal muscle and adipose tissue which relates to higher mortality in cancer patients. Here, the authors show in a lung cancer murine model that both ActRIIB signalling inhibition and restoring appetite are necessary to revert cachexia and improve survival in female mice.
- Andre Lima Queiroz
- , Ezequiel Dantas
- & Marcus D. Goncalves
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Article
| Open AccessClub cells employ regeneration mechanisms during lung tumorigenesis
Lung adenocarcinoma is a highly plastic tumour type. Here, the authors use single cell RNA sequencing to show that Club cells use regeneration mechanisms to develop tumours after an epigenetic switch towards an AT2-like phenotype shown by methylome analysis.
- Yuanyuan Chen
- , Reka Toth
- & Rocio Sotillo
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Article
| Open AccessTargeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer
Mutant KRAS (KM) is associated with poor prognosis in lung cancer and reported to promote lipid metabolism. Here, the authors show that fatty acid synthesis, which provides lipids to repair oxidized phospholipids through the FASN-Lands cycle axis, is a specific vulnerability for KM lung cancer.
- Caterina Bartolacci
- , Cristina Andreani
- & Pier Paolo Scaglioni
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Article
| Open AccessDevelopment of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment
Only a minority of patients with non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitors. Here the authors design a nanosystem for the co-delivery of a PLK1 inhibitor and PD-L1 antibody, showing anti-tumor immune responses in preclinical lung cancer models.
- Moataz Reda
- , Worapol Ngamcherdtrakul
- & Wassana Yantasee
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Article
| Open AccessIntegration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer
Some cancer patients with impaired HLA-I still respond to immunotherapy. Here the authors combine a cytotoxic gene signature from CD4+ and CD8+ T cells with tumor mutational burden to predict immunotherapy response in NSCLC patients, including those with HLA-LOH.
- Denise Lau
- , Sonal Khare
- & Aly A. Khan
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Article
| Open AccessAddressing challenges with real-world synthetic control arms to demonstrate the comparative effectiveness of Pralsetinib in non-small cell lung cancer
Real-world data (RWD) based control arms provide an option to compare the effectiveness of single-arm trials. By performing multiple quantitative bias analyses to alleviate concerns about trial-RWD comparability, here the authors show that the RET inhibitor pralsetinib provides survival benefit in patients with RET fusion-positive non-small cell lung cancer from the ARROW single-arm trial, (NCT03037385) when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts.
- Sanjay Popat
- , Stephen V. Liu
- & Vivek Subbiah
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| Open AccessPhasing analysis of lung cancer genomes using a long read sequencer
Long-read sequencing technologies are useful for the multifaceted task of characterising somatic mutations, including structural variants, in cancers. Here, the authors combine short and long read sequencing for the phasing analysis, which enables them to resolve the chromosomal backgrounds of somatic mutations in Japanese non-small cell lung cancers.
- Yoshitaka Sakamoto
- , Shuhei Miyake
- & Ayako Suzuki
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| Open AccessAutomated detection and segmentation of non-small cell lung cancer computed tomography images
Correct interpretation of computer tomography (CT) scans is important for the correct assessment of a patient’s disease but can be subjective and timely. Here, the authors develop a system that can automatically segment the non-small cell lung cancer on CT images of patients and show in an in silico trial that the method was faster and more reproducible than clinicians.
- Sergey P. Primakov
- , Abdalla Ibrahim
- & Philippe Lambin
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| Open AccessRegulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Immune checkpoint blockade is a promising approach to treat lung cancer, however, immune related adverse events hold back success in some patients. Here authors show that regulatory B cells fail to limit self-reactive T cells in these patients, and B cell phenotyping prior treatment may identify those at risk for these unfavourable outcomes.
- Akshay J. Patel
- , Zena N. Willsmore
- & Gary W. Middleton
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| Open AccessTargeted detection of cancer at the cellular level during biopsy by near-infrared confocal laser endomicroscopy
Radiography identifies suspicious lung nodules that are not always easy to diagnose via biopsy. Here, the authors utilize a fluorescent dye that targets the folate receptor and show using needle based endomicroscopy that it can be used to identify cancer cells during biopsy procedures
- Gregory T. Kennedy
- , Feredun S. Azari
- & Sunil Singhal
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Article
| Open AccessMolecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors
Acquired drug resistance is common during chemotherapy. Here, the authors describe the structural basis and molecular mechanism by which allosteric and clinically approved, ATP-competitive inhibitors of EGFR synergize to overcome resistance in lung cancer.
- Tyler S. Beyett
- , Ciric To
- & Michael J. Eck
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Article
| Open AccessTGS1 mediates 2,2,7-trimethyl guanosine capping of the human telomerase RNA to direct telomerase dependent telomere maintenance
Telomerase protects chromosome ends in stem cells and cancer cells. Here the authors show that Trimethylguaonsine Synthase 1 (TGS-1) – dependent trimethylguanosine capping of the RNA component of the human telomerase complex has an important role in directing telomere dependent telomere maintenance and suppressing the ALT pathway in cancer cells.
- Valentina Buemi
- , Odessa Schillaci
- & Stefan Schoeftner
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| Open AccessHeterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models
Molecular subtypes of small cell lung cancer characterized by neuroendocrine differentiation have been described in cell lines and primary tumors. The clinical implications of neuroendocrine subtypes in metastatic and relapsed tumors, and the extent to which the subtype distribution is recapitulated in patient-derived models remains unclear. Here, the authors integrated genomics and transcriptomics on 100 small cell cancers from a range of metastatic sites finding complex intra- and intertumoral heterogeneity, notably not recapitulated in patient-derived model systems, and distinct therapeutic vulnerabilities associated with neuroendocrine subtypes.
- Delphine Lissa
- , Nobuyuki Takahashi
- & Anish Thomas
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Article
| Open AccessGenomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts
Creating accurate models of small cell lung cancer is essential to ensure the clinical relevance of results. Here, the authors create patient derived xenograft models from 33 patients and show, through multi-omics sequencing, that these models retain the primary features of the original.
- Rebecca Caeser
- , Jacklynn V. Egger
- & Triparna Sen
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| Open AccessIntegrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes
With non-small cell lung cancer (NSCLC) being the leading cause of cancer deaths worldwide, the development of targeted therapies remains crucial. Here, the generation and multi-omics characterization of 137 NSCLC patient-derived xenografts provides a resource for potential classifications and targets.
- Shideh Mirhadi
- , Shirley Tam
- & Ming-Sound Tsao
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Article
| Open AccessKnowledge graph-based recommendation framework identifies drivers of resistance in EGFR mutant non-small cell lung cancer
Resistance to EGFR inhibitors presents a major obstacle in treating non-small cell lung cancer. Here, the authors develop a recommender system ranking genes based on trade-offs between diverse types of evidence linking them to potential mechanisms of EGFRi resistance.
- Anna Gogleva
- , Dimitris Polychronopoulos
- & Krishna C. Bulusu
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| Open AccessIntegrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression
The molecular factors that drive invasiveness and metastasis in lung adenocarcinoma (LUAD) are not completely understood. Here, the authors use an integrative network approach to identify a gene signature of invasiveness in LUAD, and reveal Aurora kinases as master regulators of invasion.
- Seungyeul Yoo
- , Abhilasha Sinha
- & Charles A. Powell
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| Open AccessClinical and genomic features of Chinese lung cancer patients with germline mutations
Germline variants that predispose to lung cancer have been mostly studied in Western populations, but data from Chinese patients is lacking. Here the authors analyze lung cancer germline variants in 1794 Chinese patients, finding exclusive variants or with different frequency compared to TCGA data.
- Wenying Peng
- , Bin Li
- & Lin Wu
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Article
| Open AccessLKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
LKB1 tumour suppressor gene is frequently mutated in lung adenocarcinoma. Here the authors show that in genetically engineered mouse models of lung cancer Lkb1 restoration induces growth arrest and drives neoplastic cells toward a more differentiated and less proliferative alveolar type II cell-like state via C/EBP-mediated reprogramming.
- Christopher W. Murray
- , Jennifer J. Brady
- & Monte M. Winslow
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Article
| Open AccessΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer
The mechanistic role regulated by the oncogene ∆Np63 in lung cancer development is currently unclear. Here, the authors show that ΔNp63 is pro-tumorigenic in lung adenocarcinoma as well as squamous cell carcinoma, and maintains lung cancer progenitor cells via regulation of super-enhancer-associated genes, including BCL9L
- Marco Napoli
- , Sarah J. Wu
- & Elsa R. Flores
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Article
| Open AccessThe histologic phenotype of lung cancers is associated with transcriptomic features rather than genomic characteristics
The molecular determinants of lung cancer histologic subtypes are not well understood. Here the authors analyze lung cancers of mixed histology and find that histologic subtypes are associated with transcriptomic features rather than genomic profiles in most tumors.
- Ming Tang
- , Hussein A. Abbas
- & Jianjun Zhang
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Article
| Open AccessInhibition of cytoplasmic EZH2 induces antitumor activity through stabilization of the DLC1 tumor suppressor protein
The tumor suppressor gene DLC1 can be downregulated in cancers through genetic and non-genetic mechanisms. Here, the authors show cytoplasmic EZH2 can directly methylate and destabilize the DLC1 protein, and EZH2 inhibition can increase the DLC1 protein half-life at least 20-fold.
- Brajendra K. Tripathi
- , Meghan F. Anderman
- & Douglas R. Lowy
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| Open AccessPlatelet PD-L1 reflects collective intratumoral PD-L1 expression and predicts immunotherapy response in non-small cell lung cancer
The definition of biomarkers to predict therapy responses to immune-checkpoint inhibitors represent an unmet clinical need. Here the authors provide evidences that platelet-derived PD-L1 could serve as a prognostic and predictive biomarker in patients with non-small cell lung cancer.
- Clemens Hinterleitner
- , Jasmin Strähle
- & Lars Zender
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| Open AccessDynamic recurrence risk and adjuvant chemotherapy benefit prediction by ctDNA in resected NSCLC
ctDNA has been shown to identify minimal residual disease (MRD) and is thus dynamically monitored in different types of tumours. Here, the authors show that serial longitudinal ctDNA analysis can be used as a tool to detect MRD, inform the use of adjuvant therapy, and predict recurrence risk in lung cancer.
- Bin Qiu
- , Wei Guo
- & Jie He
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Article
| Open AccessSingle-cell analysis of diverse immune phenotypes in malignant pleural effusion
Detailed immune cell subset identification in human lung (malignant pleural effusion) MPE is important for diagnosis and prognosis. Here the authors use single cell RNA sequencing to identify immune cell types within MPE and show differential gene expression compared to circulating immune cells in blood.
- Zhong-Yin Huang
- , Ming-Ming Shao
- & Huan-Zhong Shi
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Article
| Open AccessCold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer
Small-cell lung cancer (SCLC) is an aggressive disease with limited therapeutic options. Here the authors perform an immunogenomic analysis of limited-stage SCLC, revealing a homogeneous mutational landscape, but limited T-cell infiltration and a cold and heterogeneous T cell repertoire.
- Ming Chen
- , Runzhe Chen
- & Jianjun Zhang
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Article
| Open AccessDeciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing
The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.
- Zhoufeng Wang
- , Zhe Li
- & Weimin Li
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Article
| Open AccessEvolutionary metabolic landscape from preneoplasia to invasive lung adenocarcinoma
Metabolic reprogramming occurs during tumor progression. Here the authors decipher metabolic trajectories from preneoplasia to lung adenocarcinoma in tumor samples and identify plasma metabolites as potential predictive biomarkers for early detection.
- Meng Nie
- , Ke Yao
- & Zeping Hu
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Article
| Open AccessGenomic signatures define three subtypes of EGFR-mutant stage II–III non-small-cell lung cancer with distinct adjuvant therapy outcomes
Adjuvant gefitinib improves outcomes in non-small cell lung cancer (NSCLC) patients compared to chemotherapy, but not in all cases. Here, the authors find genomic biomarkers of response to gefitinib in NSCLC patients from the ADJUVANT trial, and propose a score to stratify them by potential benefit from the treatment.
- Si-Yang Liu
- , Hua Bao
- & Yi-Long Wu
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Article
| Open AccessDysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer
EGFR mutant lung tumours do not respond favourably to immunotherapy. Here, using single cell sequencing, the authors find that tissue resident memory CD8+ T like cells are reduced in the immune landscape of EGFR mutant tumours in comparison to wild type tumours and the presence of these cells may predict response to immunotherapy.
- Jae-Won Cho
- , Seyeon Park
- & Hye Ryun Kim
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Article
| Open AccessFBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth
Aberrant EGFR activation is commonly found in non-small cell lung cancer (NSCLC). Here the authors show that E3 ubiquitin ligase FBXL2 targets EGFR and EGFR tyrosine kinase inhibitor (TKI)-resistant mutants for proteasome-mediated degradation to inhibit EGFR-driven NSCLC growth and TKI resistance.
- Mengmeng Niu
- , Jing Xu
- & Zhi-Xiong Jim Xiao
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Article
| Open AccessCharacterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry
The tumour microenvironment (TME) may change in response to cancer treatments such as KRAS G12C inhibition, with potential implications for combination therapies. Here, the authors provide an antibody panel and workflow for analysing the TME with imaging mass cytometry in pre-clinical mouse models.
- Febe van Maldegem
- , Karishma Valand
- & Julian Downward
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Article
| Open AccessA comprehensive map of alternative polyadenylation in African American and European American lung cancer patients
Alternative polyadenylation (APA) regulates the length of the 3′UTR of mRNA. Here, the authors describe a method to accurately measure APA in tumours and apply this method to investigate the differences in APA in African American and European American lung cancer samples.
- Adriana Zingone
- , Sanju Sinha
- & Bríd M. Ryan
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Article
| Open AccessMulti-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer
Multi-region sequencing of small cell lung cancers (SCLC) can improve our understanding of the disease. Here the authors analyse 120 multi-region samples from 40 SCLC patients with whole exome sequencing and characterise their mutational burden, evolution, heterogeneity, and potential prognostic biomarkers.
- Huaqiang Zhou
- , Yi Hu
- & Ningning Zhou
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Article
| Open AccessIntegrin-αV-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade
Response to PD-1 checkpoint blockade is unpredictable in lung cancer patients. Here authors show in human lung and mouse tumour models that low or absent αV integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-β activation and hence increased infiltration of anti-tumour CD8+ T cells.
- Ines Malenica
- , Julien Adam
- & Fathia Mami-Chouaib
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Article
| Open AccessDetection and characterization of lung cancer using cell-free DNA fragmentomes
DNA from tumour cells can be detected in the blood of cancer patients. Here, the authors show that cell free DNA fragmentation patterns can identify lung cancer patients and when this information is further interrogated it can be used to predict lung cancer histological subtype.
- Dimitrios Mathios
- , Jakob Sidenius Johansen
- & Victor E. Velculescu
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Article
| Open AccessNodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer
Granulomatous/sarcoid-like lesions have been reported in patients treated with immune checkpoint inhibitors (ICIs). Here the authors report the occurrence of “nodal immune flare”, an apparent radiological cancer progression in the nodes characterized by the absence of cancer and the presence of non-caseating granulomas, in patients with non-small cell lung cancer following neoadjuvant ICI treatment.
- Tina Cascone
- , Annikka Weissferdt
- & Boris Sepesi
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Article
| Open AccessUSP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade
The cancer cell-extrinsic roles of deubiquitinases are unclear. Here the authors show that deubiquitinase USP12 downregulation contributes to development of an immune-suppressive tumour microenvironment in KRAS-driven lung cancers and mechanistically this is through the insufficient deubiquitination of the NF-κB inhibitor, PPM1B.
- Zhaojuan Yang
- , Guiqin Xu
- & Yongzhong Liu
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Article
| Open AccessIntegrative oncogene-dependency mapping identifies RIT1 vulnerabilities and synergies in lung cancer
RIT1 mutations are mutually exclusive with other lung cancer drivers and lack targeted therapies. Here the authors examine genetic dependencies of mutant RIT1 with genome-wide CRISPR screens, revealing synergy between RIT1 and YAP1, and increased sensitivity to Aurora kinase inhibitors.
- Athea Vichas
- , Amanda K. Riley
- & Alice H. Berger
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Article
| Open AccessThe integrated stress response is tumorigenic and constitutes a therapeutic liability in KRAS-driven lung cancer
The Integrated Stress Response (ISR) is a cytoprotective pathway upregulated in many cancers. Here the authors show that the activation of PERK/p-eIF2α arm of ISR enhances ERK phosphorylation through translation repression of DUSP6, thus resulting in KRAS-driven lung tumorigenesis.
- Nour Ghaddar
- , Shuo Wang
- & Antonis E. Koromilas