Featured
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Article
| Open AccessMolecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting
PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- , Xiaorong Gu
- & Jaroslaw P. Maciejewski
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Article
| Open AccessComprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
IFNγ signaling is important in the pathogenesis and immune response, emphasizing the need for investigation of its role. Here, the authors show that IFNγ plays a key role in shaping immune microenvironment in AML and developing resistance, providing insights for potential therapeutic strategies.
- Bofei Wang
- , Patrick K. Reville
- & Hussein A. Abbas
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Article
| Open AccessSerum amyloid A promotes glycolysis of neutrophils during PD-1 blockade resistance in hepatocellular carcinoma
The reasons for why hepatocellular carcinoma (HCC) is unresponsive to anti-PD-1 inhibition in some patients is not fully understood. Here the authors use human samples and mice tumour models to implicate serum amyloid A and STAT3 signalling involvement in the resistance to anti-PD1 immunotherapy in HCC.
- Meng He
- , Yongxiang Liu
- & Ning Lyu
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Article
| Open AccessThe ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models.
- Elizabeth L. Hardaker
- , Emilio Sanseviero
- & Simon T. Barry
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Article
| Open AccessInfluence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial
MIND-DC was a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived natural dendritic cell (nDC)-based therapy in patients with stage III melanoma, showing that nDC-induced immune responses did not translate into survival benefit. Here the authors report that, despite randomization, baseline differences in fecal metagenomics and serum metabolomics profiles between treatment arms might have influenced the clinical outcome of the trial.
- Carolina Alves Costa Silva
- , Gianmarco Piccinno
- & I. Jolanda M. de Vries
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Article
| Open AccessRepeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial
Recent work indicates that drug delivery to the brain can be improved through disruption of the blood brain barrier using low intensity pulsed ultrasound. Here, the authors report a phase I/II clinical trial investigating the combination of a nine-emitter implantable ultrasound device and carboplatin in patients with recurrent glioblastoma.
- Alexandre Carpentier
- , Roger Stupp
- & Ahmed Idbaih
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Article
| Open AccessMicrobes translocation from oral cavity to nasopharyngeal carcinoma in patients
Oral microbes in non-oral locations are noted across various cancers. This study highlights the abnormal translocation of oral microbes to the nasopharynx, raising the risk of nasopharyngeal cancer by remodeling the tumor microenvironment and potentially influencing EBV infection.
- Ying Liao
- , Yan-Xia Wu
- & Wei-Hua Jia
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Article
| Open AccessTumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 in head and neck cancer
Tumor histocultures have been exploited as tools to predict response to cancer therapy. Here the authors report the development and testing of a tumor histoculture platform to study response to immune checkpoint inhibitors in head and neck squamous cell carcinoma.
- Nandini Pal Basak
- , Kowshik Jaganathan
- & Satish Sankaran
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Article
| Open AccessStructure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies
The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.
- Mathieu Ferrari
- , Matteo Righi
- & Martin Pule
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Article
| Open AccessPlasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma
Acquired resistance to immune checkpoint inhibitors represents an important clinical challenge. Here, in a pancreatic ductal adenocarcinoma model of acquired resistance to immunotherapy, the authors show that plasticity-induced repression of Irf6 is associated with tumor cell-intrinsic resistance to cytotoxic T-cell activity.
- Il-Kyu Kim
- , Mark S. Diamond
- & Ben Z. Stanger
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Article
| Open AccessClinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort
CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort.
- Anwaar Saeed
- , Robin Park
- & Azhar Saeed
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Article
| Open AccessMulti-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features
The characterisation of the molecular features of multiple myeloma (MM) remains challenging. Here, the authors identify a subset of MM patients with a dismal clinical outcome, harbouring both chromosomes 1q CN gain and 13 CN loss and overexpressing CCND2.
- Carolina Terragna
- , Andrea Poletti
- & Michele Cavo
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Article
| Open AccessSintilimab with two cycles of chemotherapy for the treatment of advanced squamous non-small cell lung cancer: a phase 2 clinical trial
Combining standard 4-6 cycles of chemotherapy with immune checkpoints inhibitors has shown to improve survival in patients with non-small cell lung cancer (NSCLC), however increased toxicities have also been reported. Here the authors report the results of a phase 2 trial of sintilimab (anti-PD1) with two cycles of chemotherapy for treatment of previously untreated advanced squamous NSCLC.
- Mina Zhang
- , Guowei Zhang
- & Huijuan Wang
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Article
| Open AccessNeoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial
Immunotherapy with immune checkpoint inhibitors and targeted therapy with BRAF and MEK inhibition have revolutionized the treatment of melanoma. Here the authors report the results of a phase II trial of neoadjuvant cobimetinib (MEK inhibitor) and atezolizumab (anti-PD-L1) with or without the BRAF inhibitor vemurafenib in patients with resectable Stage III melanoma.
- Tina J. Hieken
- , Garth D. Nelson
- & Matthew S. Block
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Article
| Open AccessTissue-location-specific transcription programs drive tumor dependencies in colon cancer
Cancers of the same tissue type are characterized with different molecular features depending on anatomical location. Here, the authors show that proximal and distal colon stem cells have distinct transcriptional programs mediated by the transcription factor CDX2, with differential roles in colon cancers based on anatomical location.
- Lijing Yang
- , Lei Tu
- & Hariharan Easwaran
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Article
| Open AccessGene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer
Immune checkpoint inhibitor treatment improves overall survival in metastatic urothelial cancer, but response of individual patients varies significantly. Authors here perform whole-genome DNA and bulk RNA sequencing on samples from metastatic tumours and based on these data, they set up a single metric, T cell-to-stroma enrichment (TSE) score, that reflects the relative abundance of T cells versus stromal cells and their products, accurately predicting therapeutic outcome.
- Maud Rijnders
- , J. Alberto Nakauma-González
- & Martijn P. Lolkema
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Article
| Open AccessEpigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open AccessOncoprotein SET-associated transcription factor ZBTB11 triggers lung cancer metastasis
The molecular mechanisms of lung cancer metastasis remain incompletely understood. Here the authors show that the transcription factor ZBTB11 drives metastasis in preclinical models of lung cancer both through SE translocation (SET)-dependent and independent manner.
- Wenbin Xu
- , Han Yao
- & Donglai Wang
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Article
| Open AccessThe molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2.
Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.
- Stephan Spahn
- , Fabian Kleinhenz
- & Michael Bitzer
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Article
| Open AccessResidual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway
An important contribution of cancer associated fibroblasts (CAFs) in regulating chemoresistance has been reported. Here the authors investigate the impact of chemotherapy on CAF subsets in patients with high-grade serous ovarian cancer, suggesting that residual ANTXR1+ myofibroblasts are associated with inhibition of anti-tumor immunity.
- Monika Licaj
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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Article
| Open AccessCAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes
A main challenge for the use of CAR-T in solid tumours is the identification of surface proteins as feasible targets. Here, the authors show TYRP1 as a target for CAR-T cell therapy in preclinical models of cutaneous, acral and uveal melanoma.
- Sameeha Jilani
- , Justin D. Saco
- & Cristina Puig-Saus
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Article
| Open AccessUnraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses
Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.
- Seong Eun Lee
- , Seongyeol Park
- & Yea Eun Kang
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Article
| Open AccessTargeting DNA2 overcomes metabolic reprogramming in multiple myeloma
Multiple myeloma (MM) cancer cells can develop different resistance mechanisms to therapies inducing DNA-damage. Here, the authors show that the mitochondrial DNA repair protein DNA2 promotes MM cells survival after DNA damage-induced metabolic reprogramming.
- Natthakan Thongon
- , Feiyang Ma
- & Simona Colla
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Article
| Open AccessTracing back primed resistance in cancer via sister cells
Transcriptional cell states can drive treatment resistance in cancer. Here, the authors develop ReSisTrace to predict cell states that are primed to resist ovarian cancer treatment and validate their findings using small molecule inhibitors.
- Jun Dai
- , Shuyu Zheng
- & Anna Vähärautio
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Article
| Open AccessIntegrating leiomyoma genetics, epigenomics, and single-cell transcriptomics reveals causal genetic variants, genes, and cell types
Here the authors identify gene targets and causal cell types affected by genetic risk loci in uterine fibroids by combining meta-analysis on existing fibroid genome-wide association studies and integrated the identified risk loci and potentially causal single nucleotide polymorphisms with epigenomics, transcriptomics, 3D chromatin organization from diverse cell types as well as primary uterine fibroids patient’s samples.
- Kadir Buyukcelebi
- , Alexander J. Duval
- & Mazhar Adli
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Article
| Open AccessA 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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Article
| Open AccessTumor reactive γδ T cells contribute to a complete response to PD-1 blockade in a Merkel cell carcinoma patient
Immune checkpoint blockade cancer therapy has been designed to enable tumor killing by conventional αβ T cells. Here authors show that in a Merkel cell carcinoma patient showing complete response to anti-PD-1 treatment, innate-like γδ T cells that specifically recognize the tumor cells expand, and likely contribute to therapeutic success.
- Scott C. Lien
- , Dalam Ly
- & Pamela S. Ohashi
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Article
| Open AccessRedox-responsive polymer micelles co-encapsulating immune checkpoint inhibitors and chemotherapeutic agents for glioblastoma therapy
Immune checkpoint blockade-based immunotherapy has shown limited efficacy in patients with glioblastoma (GBM). Here the authors describe the design of redox-responsive micelles for increasing the delivery of paclitaxel and anti-PD-L1 in the brain, showing improved anti-tumor immune response in preclinical GBM models.
- Zhiqi Zhang
- , Xiaoxuan Xu
- & Shenghong Ju
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Article
| Open AccessThe anti-PD-L1/CTLA-4 bispecific antibody KN046 in combination with nab-paclitaxel in first-line treatment of metastatic triple-negative breast cancer: a multicenter phase II trial
KN046 is a recombinant anti-PD-L1/CTLA-4 bispecific antibody that has shown clinical activity in different advanced solid tumors. Here the authors report the results of a phase II study of KN046 in combination with nab-paclitaxel as first-line treatment of metastatic triple-negative breast cancer.
- Qiao Li
- , Jiaxuan Liu
- & Binghe Xu
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Article
| Open AccessCamrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial
The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Here the authors report the results of a phase II clinical trial of camrelizumab (anti-PD1) and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma.
- Hu Liang
- , Yao-Fei Jiang
- & Yan-Qun Xiang
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Article
| Open AccessTargeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma
Immune checkpoint inhibitors have now been approved for the treatment of advanced hepatocellular carcinoma (HCC), however only a minority of patients appear to benefit. Here the authors report that RNase1 levels predict response to nivolumab (anti-PD1) in patients with HCC and that RNase 1 overexpression correlates with an immunosuppressive tumor microenvironment in HCC preclinical models.
- Chunxiao Liu
- , Chenhao Zhou
- & Mien-Chie Hung
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Article
| Open AccessMutation-specific CAR T cells as precision therapy for IGLV3-21R110 expressing high-risk chronic lymphocytic leukemia
The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.
- Florian Märkl
- , Christoph Schultheiß
- & Mascha Binder
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Article
| Open AccessNuclear to cytoplasmic transport is a druggable dependency in MYC-driven hepatocellular carcinoma
The MYC oncogene is activated in the majority of human cancers and has proven challenging to target therapeutically. In this study, the authors identify genome-wide MYC synthetic-lethal interactions that could serve as potential alternative targets for the treatment of MYC-driven cancers.
- Anja Deutzmann
- , Delaney K. Sullivan
- & Dean W. Felsher
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Article
| Open AccessDurvalumab and guadecitabine in advanced clear cell renal cell carcinoma: results from the phase Ib/II study BTCRC-GU16-043
Preclinical studies have suggested the synergistic effect of epigenetic modulators and immunotherapy. Here the authors report the results of a phase Ib/II trial of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma.
- Yousef Zakharia
- , Eric A. Singer
- & Ajjai Alva
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Article
| Open AccessNeutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages
Ceramide, a central molecule in sphingolipid metabolism, has been shown to affect the development and functionality of myeloid cells. Here the authors report that myeloid deficiency of neutral ceramidase (NcDase), the enzyme converting ceramide into sphingosine, induces an immunosuppressive phenotype of tumor associated macrophages, linked to T cell exhaustion in breast cancer preclinical models.
- Rui Sun
- , Chao Lei
- & Zhongbin Deng
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Article
| Open AccessToripalimab plus capecitabine in the treatment of patients with residual nasopharyngeal carcinoma: a single-arm phase 2 trial
Although most patients achieve complete response after standard-of-care treatment, residual disease in patients with nasopharyngeal carcinoma is associated with poor prognosis. Here the authors report the results of a phase 2 trial of toripalimab (anti-PD1) plus capecitabine for patients with residual nasopharyngeal carcinoma.
- Xun Cao
- , Hao-Yang Huang
- & Xing Lv
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Article
| Open AccessA wearable electrostimulation-augmented ionic-gel photothermal patch doped with MXene for skin tumor treatment
A wearable biological patch capable of producing multiple responses to light and electricity without interfering with daily activities is desired for skin cancer treatment but remains elusive. Herein, the authors report a skin-mountable and dual-responsive electrothermal patch for melanoma treatment by the co-therapy of photothermal and electrical stimulations.
- Xingkai Ju
- , Jiao Kong
- & Yongdong Jin
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Article
| Open AccessMHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides
Defective immune responses have been reported in cutaneous T-cell lymphoma (CTCL). Here the authors show that in patients with mycosis fungoides, the most common CTCL, malignant T cells upregulate MHC-I as a mechanism to evade NK-mediated immunity.
- Yun-Tsan Chang
- , Pacôme Prompsy
- & Emmanuella Guenova
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Article
| Open AccessDurvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial
Response rates to immune-checkpoint inhibitors in patients with advanced sarcoma remain modest. Here the authors report the results of a phase 2 study of durvalumab (anti-PD-L1) in combination with the anti-VEGF receptor tyrosine-kinase inhibitor pazopanib in unselected advanced sarcomas with correlative genomic analysis.
- Hee Jin Cho
- , Kum-Hee Yun
- & Hyo Song Kim
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Article
| Open AccessA telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer
Therapeutic options for small cell lung cancer (SCLC) are limited. Here the authors show that a telomere-targeting drug, 6-Thio-2’-deoxyguanosine, inhibits growth of SCLC tumors by inducing telomere dysfunction preferentially in cancer initiating cells and promoting anti-tumor immune responses.
- Buse Eglenen-Polat
- , Ryan R. Kowash
- & Esra A. Akbay
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Article
| Open AccessMacro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- , Lei-Lei Wu
- & Jia Fan
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Article
| Open AccessBispecific BCMA/CD24 CAR-T cells control multiple myeloma growth
BCMA-specific CAR T-cell therapies have shown high response rates in multiple myeloma (MM), however the majority of patients still relapse. Here the authors show that CD24-positive MM cells increase after BCMA-CAR-T treatment in patients, and that dual-targeted BCMA/CD24 CAR-T cells can improve anti-tumor efficacy in MM preclinical models.
- Fumou Sun
- , Yan Cheng
- & Fenghuang Zhan
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Article
| Open AccessGeneration and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Clonal Vb2 usage is common among patients with mature T cell lymphoma. Here the authors report the generation of allogeneic CAR-T cells selectively targeting TCR Vb2+ on malignant T cells, with limited normal T cell destruction.
- Jingjing Ren
- , Xiaofeng Liao
- & Michael Girardi
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Article
| Open AccessCarcinoembryonic antigen-expressing oncolytic measles virus derivative in recurrent glioblastoma: a phase 1 trial
Oncolytic measles virus (MV) vaccine strains have shown preclinical antitumor activity against glioblastoma (GBM). Here the authors report the results of a phase 1 trial of intratumoral administration of a MV strain engineered to express the carcinoembryonic antigen in patients with recurrent GBM including assessment of viral replication and proinflammatory remodeling of the treated tumors.
- Evanthia Galanis
- , Katharine E. Dooley
- & Ian F. Parney
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Article
| Open AccessDesign-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists
Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.
- Arun Chandramohan
- , Hubert Josien
- & Anthony W. Partridge
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Article
| Open AccessMutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death
Oncogenic KRAS mutations can dictate the formation of an immune-suppressive tumor microenvironment. Here the authors report that, in KRAS mutant colorectal cancer, the upregulation of circATXN7 in tumor-specific cytotoxic T lymphocytes is associated with increased sensitivity to activation-induced cell death and resistance to immunotherapy.”
- Chi Zhou
- , Wenxin Li
- & Huashan Liu
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Article
| Open AccessThe HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.
- Gail D. Lewis
- , Guangmin Li
- & Eunpi Cho
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Article
| Open AccessCompartments in medulloblastoma with extensive nodularity are connected through differentiation along the granular precursor lineage
The mechanisms regulating the balance between proliferation and differentiation in medulloblastomas with extensive nodularity (MBEN) remain poorly understood. Here, single cell multi-omics and spatial analysis characterises the spatial tissue organisation of MBEN in the context of the developmental trajectory.
- David R. Ghasemi
- , Konstantin Okonechnikov
- & Kristian W. Pajtler
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Article
| Open AccessDistinct mesenchymal cell states mediate prostate cancer progression
The components of the tumour microenvironment contribute to prostate cancer initiation and progression. Here the authors perform single-cell RNA sequencing and spatial transcriptomics analysis of prostate cancer stroma from mouse models at different stages of the disease and develop a gene signature to predict distant metastasis in patients.
- Hubert Pakula
- , Mohamed Omar
- & Massimo Loda