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| Open AccessID1 expressing macrophages support cancer cell stemness and limit CD8+ T cell infiltration in colorectal cancer
Inhibitor of differentiation 1 (ID1) has been described as a cancer-promoting factor and also involved in the formation of an immunosuppressive tumor microenvironment. Here the authors report that ID1-expressing tumor associated macrophages favor colorectal cancer progression by promoting cancer cell stemness and CD8+ T cell exclusion.
- Shuang Shang
- , Chen Yang
- & Fang Hua
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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 AccessAnti-TACI single and dual-targeting CAR T cells overcome BCMA antigen loss in multiple myeloma
Patients with myeloma multiple treated with BCMA CAR T cells often relapse with BCMA-negative disease or antigen escape. Here the authors describe the design of TACI-directed single and dual CAR T cells with in vitro and in vivo activity against multiple myeloma, overcoming BCMA antigen loss.
- Rebecca C. Larson
- , Michael C. Kann
- & Marcela V. Maus
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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 AccessMinimal residual disease detection by next-generation sequencing of different immunoglobulin gene rearrangements in pediatric B-ALL
While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. Here, the authors investigate it using a next generation sequencing approach.
- Haipin Chen
- , Miner Gu
- & Xiaojun Xu
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| Open AccessHigh-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq
Understanding T cell behaviour in cancers is vital for improving immunotherapies. Here, the authors present spatially resolved T cell receptor sequencing (SPTCR-seq), a technology that annotates T cell receptors within the tumour ecosystem.
- Jasim Kada Benotmane
- , Jan Kueckelhaus
- & Dieter Henrik Heiland
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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 AccessSND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer
The ETS family transcription factor ERG is frequently overexpressed in prostate cancer and known to have a role in carcinogenesis, however, the underlying mechanism is less understood. Here, the authors report an interaction between ERG and SND1 as necessary for ERG-driven prostate cancer initiation using preclinical models.
- Sheng-You Liao
- , Dmytro Rudoy
- & Valeri Vasioukhin
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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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 AccessNanomedicine-based co-delivery of a calcium channel inhibitor and a small molecule targeting CD47 for lung cancer immunotherapy
Lung cancer is characterized by an immunosuppressive microenvironment, limiting responses to immunotherapies. Here the authors report the design of a pH-responsive nanomedicine for the co-delivery of a T-type calcium channel inhibitor and of a small molecule targeting CD47, promoting anti-tumor immune responses in orthotopic lung cancer preclinical models.
- Yuedong Guo
- , Qunqun Bao
- & Jianlin Shi
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Article
| Open AccessImmuno-metabolic dendritic cell vaccine signatures associate with overall survival in vaccinated melanoma patients
Efficacy of dendritic cell (DC)-based vaccines remains unsatisfactory. Here the authors analyse the transcriptomic and immune-metabolic profiles of DCs from patients enrolled in a DC vaccine trial in late-stage melanoma, suggesting that the metabolic profile of DC is associated with the immunostimulatory potential of the cancer vaccine.
- Juraj Adamik
- , Paul V. Munson
- & Lisa H. Butterfield
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Article
| Open AccessUnlocking the potential of allogeneic Vδ2 T cells for ovarian cancer therapy through CD16 biomarker selection and CAR/IL-15 engineering
Vγ9Vδ2 (Vδ2) T cells have been proposed as cell carriers for off-the-shelf CAR therapies. Here the authors describe CD16 as a biomarker for the selection of Vδ2 T cells with high levels of cytotoxicity and report the anti-tumor activity of engineered CD16high Vδ2 T cells in ovarian cancer preclinical models.
- Derek Lee
- , Zachary Spencer Dunn
- & Lili Yang
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Article
| Open AccessValidation of MSIntuit as an AI-based pre-screening tool for MSI detection from colorectal cancer histology slides
Microsatellite instability is a known risk factor for colorectal cancer development and treatment response. Here, the authors utilise deep learning to develop MSIntuit, a pre-screening tool to detect MSI from H&E stained slides.
- Charlie Saillard
- , Rémy Dubois
- & Magali Svrcek
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Article
| Open AccessMetabolic dependencies of metastasis-initiating cells in female breast cancer
Understanding the mechanisms associated with cancer metastasis may help control cancer progression. Here the authors investigate the metabolism of metastasis initiating cells in breast cancer and show that their metastatic ability relies on fatty acid oxidation and the oxidative tricarboxylic acid cycle, which in turn regulates acetyl-CoA generation and the acetylation of histones on EMT related genes.
- C. Megan Young
- , Laurent Beziaud
- & Joerg Huelsken
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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 AccessSelective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma
Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.
- Lin-Lin Zhou
- , Tao Zhang
- & Cai-Guang Yang
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Article
| Open AccessCathepsin-facilitated invasion of BMI1-high hepatocellular carcinoma cells drives bile duct tumor thrombi formation
Bile duct tumor thrombosis (BDTT) is a complication associated with advanced hepatocellular carcinoma (HCC) which can severely limits quality of life. Here, the authors develop a spontaneous BDTT mouse model to investigate the cellular original and mechanism underlying the formation of BDTT.
- Lei-Bo Xu
- , Yu-Fei Qin
- & Ping-Pui Wong
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Article
| Open AccessImmunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials
Neoadjuvant therapies with dual anti-HER2 blockade have proven effective in HER2+ breast cancer treatment. Here, the authors develop a score that integrates antigen receptor repertoire features and clinical parameters to predict prognosis after anti-HER2 neoadjuvant treatments.
- Mattia Rediti
- , Aranzazu Fernandez-Martinez
- & Christos Sotiriou
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| Open AccessMoving closer towards a comprehensive view of tumor biology and microarchitecture using spatial transcriptomics
Spatial transcriptomic profiling of cancer has enabled spatial delineation of malignant transcriptional heterogeneity, intercellular communication, and organization of microanatomical structures within the tumor microenvironment. This technical breakthrough paves the way for the development of precision diagnostic methods and targeted therapies.
- Young Min Park
- & De-Chen Lin
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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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| 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 AccessThe Lin28b/Wnt5a axis drives pancreas cancer through crosstalk between cancer associated fibroblasts and tumor epithelium
Crosstalk between tumor cells and the microenvironment is essential for tumor progression. Here, the authors show Pancreatic ductal adenocarcinoma (PDAC) epithelial cells with high level of Lin28b secrete Wnt5a to upregulate Lin28b expression in cancer-associated fibroblasts, which in turn promote growth of PDAC cells via production of PCSK9.
- Zhaoqi Shu
- , Minghe Fan
- & Ying Zhao
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Article
| Open AccessA tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development
Within gastrointestinal tissues, tuft cells, a rare population of chemo-sensory epithelial cells, can promote the activation of type 2 innate lymphoid cells (ILC2s). Here the authors show that tuft cells and ILC2s are increased during gastric cancer development and that the pharmacologic inhibition of tuft cell derived IL25 or ILC2-produced IL13 reduces gastric tumor growth.
- Ryan N. O’Keefe
- , Annalisa L. E. Carli
- & Michael Buchert
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Article
| Open AccessEnhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing
Targeted sequencing panels such as MSK-IMPACT have been successfully used to profile solid tumours in clinical settings. Here, the authors develop and implement the MSK-IMPACT Heme sequencing panel and platform to profile haematologic malignancies using paired tumor and normal tissues.
- Ryan N. Ptashkin
- , Mark D. Ewalt
- & Maria E. Arcila
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Article
| Open AccessSingle-cell morphological and topological atlas reveals the ecosystem diversity of human breast cancer
Whole-slide images (WSI) and digital pathology are valuable approaches for the analysis of tumours and their microenvironments. Here, the authors present scMTOP, a framework to characterise tumour ecosystems and intercellular relationships at the single-cell level from WSIs, which they apply to breast cancer samples.
- Shen Zhao
- , De-Pin Chen
- & Zhi-Ming Shao
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Article
| Open AccessChromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia
The molecular mechanisms underlying relapse in pediatric B-lineage acute lymphoblastic leukemia (B-ALL) patients remain to be explored. Here, the authors characterise the chromatin accessibility landscape of B-ALL and identify subtype and drug response specific patterns.
- Han Wang
- , Huiying Sun
- & Yu Liu
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Article
| Open AccessIDH1 mutation impairs antiviral response and potentiates oncolytic virotherapy in glioma
The role of human glioma IDH1 mutations in regulation of antiviral response is unclear. Here, the authors show that D2HG produced by mutant IDH1 inhibits IFN antiviral responses in glioma cells, which confers sensitivity to oncolytic virotherapy.
- Xueqin Chen
- , Jun Liu
- & Haipeng Zhang
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Article
| Open AccessIntegrated radiogenomics models predict response to neoadjuvant chemotherapy in high grade serous ovarian cancer
Response to treatment in high grade serous ovarian carcinoma (HGSOC) is highly variable. Here, the authors leverage a radiogenomic model to predict neoadjuvant chemotherapy response in HGSOC, including clinical data, medical imaging, and blood-based biomarkers such as CA-125 and ctDNA features.
- Mireia Crispin-Ortuzar
- , Ramona Woitek
- & James D. Brenton
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Article
| Open AccessBiomimetic nanovaccine-mediated multivalent IL-15 self-transpresentation (MIST) for potent and safe cancer immunotherapy
Cancer immune therapy utilizing interleukin 15 (Il-15) is hampered by the short half-life and systemic toxic effects of the cytokine. Here authors introduce a biomimetic nanovaccine, in which Il-15 and tumor-associated antigenic peptide/MHC-I complexes are co-anchored to cell membrane vesicles of dendritic cell origin, which elicits antigen-specific T cell response leading to superior anti-tumour effect in syngeneic mouse tumour models.
- Kaiyuan Wang
- , Xuanbo Zhang
- & Jin Sun
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| Open AccessNivolumab and ipilimumab in recurrent or refractory cancer of unknown primary: a phase II trial
Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.
- Maria Pouyiourou
- , Bianca N. Kraft
- & Alwin Krämer
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Article
| Open AccessNeoadjuvant camrelizumab plus nab-paclitaxel and epirubicin in early triple-negative breast cancer: a single-arm phase II trial
Recent evidence suggests the feasibility of neoadjuvant immune checkpoint inhibitors plus chemotherapy-based therapy for patients with early triple-negative breast cancer (TNBC). Here the authors report the results of a single-arm phase II trial of neoadjuvant camrelizumab (anti-PD-1) plus nab-paclitaxel and epirubicin for early TNBC.
- Chengzheng Wang
- , Zhenzhen Liu
- & Min Yan
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Article
| Open AccessSleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development
Chronic inflammation promotes the development and progression of colorectal cancer (CRC) while the underlying mechanism remains to be elucidated. Here, the authors perform in vivo transposon mutagenesis screening to identify that TNFα-activated senescence signaling acts as selective pressure to drive mutation of Cdkn2a and other senescence-related genes in inflammation-accelerated CRC.
- Kana Shimomura
- , Naoko Hattori
- & Haruna Takeda
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Article
| Open AccessMolecular 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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Article
| Open AccessA randomized controlled trial testing a virtual program for Asian American women breast cancer survivors
Virtual support methods have been shown to be an effective aid in cancer survivorship. Here, the authors created a culturally tailored information and support system for Asian American breast cancer patients and showed these resources improved quality of life.
- Eun-Ok Im
- , Wonshik Chee
- & Jun J. Mao
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Article
| Open AccessUSP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open AccessKRAS G12V neoantigen specific T cell receptor for adoptive T cell therapy against tumors
Recent evidence suggests that KRAS mutations can be source of neoantigens and elicit T cell responses. Here the authors report the identification and characterization of KRAS-G12V specific TCRs for adoptive T cell immunotherapy.
- Dan Lu
- , Yuan Chen
- & George F. Gao
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Article
| Open AccessNeuropathologist-level integrated classification of adult-type diffuse gliomas using deep learning from whole-slide pathological images
Determining glioma types directly from whole-slide images (WSIs) would be of great diagnostic utility. Here, the authors develop a deep learning model to identify diffuse glioma types from WSIs according to the 2021 WHO classification across multiple cohorts and with interpretable features.
- Weiwei Wang
- , Yuanshen Zhao
- & Zhenyu Zhang
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Article
| Open AccessSignature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer
The success of targeting KRAS for cancer therapy is limited by resistance due to compensatory mechanism, making combinatorial approaches attractive. Here, the authors use a KRAS signature drug repurposing screen and identify the multityrosine kinase PKC inhibitor Midostaurin as synergistic with MEK and KRAS inhibitors in KRAS-mutated lung adenocarcinoma.
- Irati Macaya
- , Marta Roman
- & Silve Vicent
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Article
| Open AccessDalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial
Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.
- Min Yan
- , Limin Niu
- & Huajun Li
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Article
| Open AccessDistinct and targetable role of calcium-sensing receptor in leukaemia
Several parameters in the bone marrow (BM) niche regulate leukaemic stem cell status and disease progression. Here, the authors show that calcium-sensing receptor affects the location of acute myeloid leukaemia (AML) cells in the BM niche which influences self-renewal of leukaemic stem cells and AML development
- Raquel S. Pereira
- , Rahul Kumar
- & Daniela S. Krause
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Article
| Open AccessSingle-cell analysis reveals altered tumor microenvironments of relapse- and remission-associated pediatric acute myeloid leukemia
Single-cell RNA-seq could help identify acute myeloid leukaemia (AML) patients at high risk of relapse after therapy. Here, the authors use single-cell RNA-seq from paediatric AML samples to construct a 7-gene signature that can identify malignant cells at diagnosis, which are distinctly associated with relapse or complete remission.
- Hope Mumme
- , Beena E. Thomas
- & Manoj Bhasin
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Article
| Open AccessMyoglobin-loaded gadolinium nanotexaphyrins for oxygen synergy and imaging-guided radiosensitization therapy
Researchers have been working on radiosensitizers to improve radiotherapy efficacy. Here the authors generate gadolinium nanotexaphyrins (Gd-NTs) that self-assemble and further load it with myoglobulin to relieve hypoxia, improve radiosensitization effects of Gd-coordinated Texaphyrin, and suppress tumor recurrence.
- Xiaotu Ma
- , Xiaolong Liang
- & Fan Wang
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Article
| Open AccessUncovering the complex relationship between balding, testosterone and skin cancers in men
Male-pattern baldness (MPB) is related to dysregulation of androgens. Here, authors show that MPB (but not androgens) is associated with skin cancer risk, particularly in the scalp region, suggesting that sun exposure, rather than androgens, is the main driver.
- Jue-Sheng Ong
- , Mathias Seviiri
- & Matthew H. Law
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Article
| Open AccessRepressed Blautia-acetate immunological axis underlies breast cancer progression promoted by chronic stress
Chronic stress can promote breast cancer progression. Here the authors show that a reduction in the levels of Blautia and its metabolite acetate contributes to chronic stress-promoted breast cancer progression, associated with decreased CD8 + T cell anti-tumor immunity.
- Ling Ye
- , Yuanlong Hou
- & Haiping Hao
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Article
| Open AccessPARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models
IFNγ signalling has been described as a potential driver of resistance to immune checkpoint blockade (ICB) therapy. Here the authors report that PARP14 is upregulated in chronic IFNγ-treated cancer cell models and that its inhibition restores response to anti-PD-1 therapy in preclinical cancer models.
- Chun Wai Wong
- , Christos Evangelou
- & Adam F. L. Hurlstone
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Article
| Open AccessGenome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
| Open AccessEvolutionary signatures of human cancers revealed via genomic analysis of over 35,000 patients
The identification of cancer type-specific evolutionary signatures could be used for patient stratification. Here, the authors develop a method, ASCETIC, that utilises bulk and single-cell sequencing data and identifies evolutionary signatures associated with different prognostic outcomes across different cancer types.
- Diletta Fontana
- , Ilaria Crespiatico
- & Daniele Ramazzotti
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Article
| Open AccessDeep learning-enabled realistic virtual histology with ultraviolet photoacoustic remote sensing microscopy
Oncologic tumour resection is not fully accurate. Here the authors report a label-free virtual histological imaging method based on a non-contact, reflection-mode ultraviolet photoacoustic remote sensing and scattering microscope, combined with unsupervised deep learning using a cycle-consistent GAN.
- Matthew T. Martell
- , Nathaniel J. M. Haven
- & Roger J. Zemp