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| 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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| 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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Article
| 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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| 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
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Article
| Open AccessGuadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial
The NIBIT-M4 trial was designed to assess the safety, biological and clinical activity of anti-CTLA4 ipilimumab with the DNA hypomethylating agent guadecitabine in advanced melanoma patients. Here the authors report the five-year follow-up results of the trial and an integrated multi-omics analysis of pre- and on-treatment tumor biopsies.
- Teresa Maria Rosaria Noviello
- , Anna Maria Di Giacomo
- & Michele Ceccarelli
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Article
| Open AccessDisentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study
Multiple myeloma (MM) is a haematological malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS). Here, the authors use a mechanistic model fitted to surveillance data from the United States to investigate whether variation in MM is best explained by incidence of MGUS or rate of progression to MM.
- John H. Huber
- , Mengmeng Ji
- & Su-Hsin Chang
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| Open AccessMetabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors
The functional-metabolic state of macrophages fundamentally influences the tumour microenvironment, making adoptive cell therapy with pro-inflammatory macrophages an attractive anti-tumour approach. Here authors introduce pluripotent stem cell-derived CAR-macrophage that are depleted of ACOD1, an essential gene in itaconate metabolism, which reprograms them to a pro-inflammatory state enabling enhanced anti-tumour function.
- Xudong Wang
- , Siyu Su
- & Jin Zhang
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Article
| Open AccessActivation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity
Aberrant G protein-coupled receptor (GPCR) signaling has been associated with tumor progression and metastasis. Here the authors show that depletion of the GPCR melanocortin-1 receptor (MC1R) in melanoma cells is associated with enhanced T cell infiltration and anti-tumor immune responses.
- Yazhong Cui
- , Yang Miao
- & Ting Han
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Article
| Open AccessStromal heterogeneity may explain increased incidence of metaplastic breast cancer in women of African descent
Breast cancer patients of African ancestry face worse clinical outcomes, so understanding related cellular and molecular features remains critical. Here, the authors show that stromal cells that are particularly enriched in breast cancer patients with African ancestry can trans-differentiate into different lineages and can be transformed into metaplastic carcinoma.
- Brijesh Kumar
- , Aditi S. Khatpe
- & Harikrishna Nakshatri
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Article
| Open AccessCell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy
Tumor associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment, including hepatocellular carcinoma (HCC). Here the authors show that macrophage-derived microparticles modified with a M2-like macrophage targeting peptide and loaded with the TLR7/8 agonist resiquimod reprogram TAMs from immunosuppressive to inflammatory, promoting anti-tumor immune responses in preclinical HCC models.
- Xiaoqiong Zhang
- , Zhaohan Wei
- & Lu Gan
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Article
| Open AccessMYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer
Few mouse models recapitulate the complexity of triple negative breast cancer (TNBC). Here, the authors develop and characterise a TNBC mouse model harbouring two common TNBC mutations: amplification of the oncogene MYC and deletion of the tumour suppressor PTEN.
- Zinab O. Doha
- , Xiaoyan Wang
- & Rosalie C. Sears
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Article
| Open AccessFasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
The use of immune checkpoint inhibitors is associated with a wide range of side effects. Here the authors explore the use of periodic cycles of a diet that mimics fasting and see reduction in side effects caused by a range of immune checkpoint blockade antibodies in a preclinical cancer model.
- S. Cortellino
- , V. Quagliariello
- & V. D. Longo
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Article
| Open AccessTriplet maintenance therapy of olaparib, pembrolizumab and bevacizumab in women with BRCA wild-type, platinum-sensitive recurrent ovarian cancer: the multicenter, single-arm phase II study OPEB-01/APGOT-OV4
Even in patients who are initially sensitive, patients treated with platinum-based therapies often go on to relapse and have limited treatment options. Here, the authors report the efficacy and safety of a phase II trial investigating olaparib, pembrolizumab and bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer.
- Yoo-Na Kim
- , Boram Park
- & Jung-Yun Lee
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Article
| Open AccessThe mutational landscape of the adult healthy parous and nulliparous human breast
While many tissues have been investigated for natural somatic mutations, human breast tissue has not been well studied. Here, the authors characterize somatic mutations in human breast tissue, finding effects of age and parity.
- Biancastella Cereser
- , Angela Yiu
- & Justin Stebbing
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Article
| Open AccessAtezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial
Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.
- Arta M. Monjazeb
- , Megan E. Daly
- & Karen Kelly
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Article
| Open AccessLow-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models
Although CAR T therapy has greatly improved the therapeutic prospects for haematological malignancies, it is not yet widely used for solid tumors, such as prostate cancer. Here, using prostate cancer patient-derived xenografts, the authors demonstrate the efficacy of CAR T cells specific for Lewis Y antigen when combined with low-dose carboplatin.
- L. H. Porter
- , J. J. Zhu
- & G. P. Risbridger
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Article
| Open AccessAcquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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Article
| Open AccessDNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability
Genomic instability can induce an anti-tumour immune response via activation of the cGAS-STING pathway following the formation of micronuclei (MN). Here, the authors identify a role for DNAJA2 in maintenance of chromosomal segregation. Loss of which increased MN formation and cGAS-STING pathway activation, increasing response to immune checkpoint blockade.
- Yaping Huang
- , Changzheng Lu
- & Guo-Min Li
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Article
| Open AccessCoordinated 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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Article
| Open AccessMLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia
Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.
- Nicholas T. Crump
- , Alastair L. Smith
- & Thomas A. Milne
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Article
| Open AccessImmune stress suppresses innate immune signaling in preleukemic precursor B-cells to provoke leukemia in predisposed mice
Immunological stressors are linked to the transformation of preleukemic B cells to B-cell acute lymphoblastic leukemia. Here the authors show a dysregulation of innate immune signaling in preleukemic precursor B cells and link to the development of B-cell acute lymphoblastic leukemia in a murine model.
- Marta Isidro-Hernández
- , Ana Casado-García
- & Isidro Sánchez-García
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Article
| Open AccessAcquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype
Acquired resistance to immune checkpoint inhibitors limits therapeutic success in non-small-cell lung cancer, however, the underpinning immune parameters are largely unknown. Here authors distinguish resistance types based on immune cell infiltration, immune checkpoint molecule and cytokine expression level, using paired samples from patients in the sensitive and in the resistant disease phase.
- Stefanie Hiltbrunner
- , Lena Cords
- & Alessandra Curioni-Fontecedro