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VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.
- Thomas Thisted
- , F. Donelson Smith
- & Edward H. van der Horst
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| Open Access
Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment
CREBBP and KMT2D mutations frequently co-occur in B cell lymphomas with unclear significance. Here the authors show that they cooperate to skew B cell fate decisions and induce a CD8-depleted immune-evasive microenvironment to facilitate lymphomagenesis.
- Jie Li
- , Christopher R. Chin
- & Ari M. Melnick
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| Open Access
Spatial transcriptomics reveals discrete tumour microenvironments and autocrine loops within ovarian cancer subclones
Intratumoural heterogeneity in high-grade serous ovarian carcinoma (HGSOC) remains to be explored. Here, the authors perform spatial transcriptomics and reveal a high degree of subclonal heterogeneity in HGSOC.
- Elena Denisenko
- , Leanne de Kock
- & Alistair R. R. Forrest
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| Open Access
Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk
Obesity represents a risk factor for cancer and compromises immune function, however the mechanisms linking the two together are not fully known. Here authors show in a mouse sarcoma model that obesity increases tumour incidence, impairs intra-tumoral T cell immunity but paradoxically increases sensitivity to immune therapy via impairing immunoediting.
- Alexander Piening
- , Emily Ebert
- & Ryan M. Teague
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| Open Access
Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer
The heterogeneity of cancer associated fibroblasts (CAFs) in breast cancer has been previously described. Here the authors provide further insights into the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer.
- Hugo Croizer
- , Rana Mhaidly
- & Fatima Mechta-Grigoriou
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| Open Access
SpiDe-Sr: blind super-resolution network for precise cell segmentation and clustering in spatial proteomics imaging
Imaging mass cytometry (IMC) is a powerful single-cell resolution platform for targeted spatial proteomics, but it can be constrained by imaging noise and resolution. Here, the authors propose SpiDe-Sr, a super-resolution network embedded with a denoising module for IMC spatial resolution enhancement.
- Rui Chen
- , Jiasu Xu
- & Xianting Ding
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Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma
Distinct genetic mutations can shape the tumor immune microenvironment. Here the authors generate preclinical mouse models of hepatocellular carcinoma bearing clinically-relevant oncogenic driver combinations, identifying myeloid cell-centric exploitable therapeutic vulnerabilities.
- Christel F. A. Ramirez
- , Daniel Taranto
- & Leila Akkari
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Spatial relationships in the urothelial and head and neck tumor microenvironment predict response to combination immune checkpoint inhibitors
Spatial positioning of cells within the tumour microenvironment may have a function in the success of immune checkpoint immunotherapy (ICI). Here the authors analyse spatial relationships from immunohistochemistry samples prior to ICI therapy and show that CD8 T cell or macrophage proximity to cancer cells is associated with better responses.
- Alberto Gil-Jimenez
- , Nick van Dijk
- & Lodewyk F. A. Wessels
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Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Cancer associated fibroblasts can shape the tumor microenvironment (TME) and modulate immune infiltration. Here the authors characterize the TME in preclinical models of softtissue sarcomas, identifying a subset of “glycolytic” cancer-associated fibroblasts that inhibit cytotoxic T cell infiltration into the tumor parenchyma.
- Marina T. Broz
- , Emily Y. Ko
- & Jlenia Guarnerio
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| Open Access
The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous drug resistant disease
Here, the authors develop a hybrid agent-based model to quantify the contributions of intrinsic cellular mechanisms and bone ecosystem factors to therapy resistance in multiple myeloma. They show that intrinsic mechanisms are essential for resistance, and that the bone microenvironment provides a protective niche that increases the likelihood.
- Ryan T. Bishop
- , Anna K. Miller
- & David Basanta
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Article
| Open Access
Spatially-resolved transcriptomics reveal macrophage heterogeneity and prognostic significance in diffuse large B-cell lymphoma
Macrophages are abundant in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Here, the authors use spatial transcriptomics to characterize macrophages in DLBCL and reactive lymphoid tissues, and propose six spatially-derived macrophage signatures that are associated with features like cell of origin and clinical outcomes.
- Min Liu
- , Giorgio Bertolazzi
- & Anand D. Jeyasekharan
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Article
| Open Access
Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Article
| Open Access
Domain generalization enables general cancer cell annotation in single-cell and spatial transcriptomics
Efficient and accurate annotation of malignant cells is crucial for single-cell and spatial transcriptomics in cancer. Here, the authors develop Cancer-Finder, a deep-learning algorithm that can identify malignant cells in cancer single-cell and spatial transcriptomics data with speed and precision.
- Zhixing Zhong
- , Junchen Hou
- & Jia Song
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The 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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| Open Access
Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma
The behavior of exosomes in vivo is not completely elucidated. Here the authors develop a genetically engineered mouse model (ExoBow) to trace the distribution of exosomes, showing local and inter-organ communication networks, either specific or shared between healthy pancreas and pancreatic ductal adenocarcinoma.
- Bárbara Adem
- , Nuno Bastos
- & Sonia A. Melo
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| Open Access
Proteomic characterization identifies clinically relevant subgroups of soft tissue sarcoma
The molecular characterisation of soft tissue sarcomas (STSs) across diverse populations remains crucial. Here, the authors perform a proteomics and phosphoproteomics analysis of 272 Chinese STS patients across 12 subtypes, and obtain insights related to progression, metastasis, and immune signatures.
- Shaoshuai Tang
- , Yunzhi Wang
- & Chen Ding
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| Open Access
Residual 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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| Open Access
Intercellular transfer of cancer cell invasiveness via endosome-mediated protease shedding
The matrix metalloprotease MT1-MMP drives cancer metastasis. Here, the authors demonstrate how invasive cancer cells instigate non-invasive neighbouring cells to become degradative and invasive by transferring catalytically active MT1-MMP fragments.
- Eva Maria Wenzel
- , Nina Marie Pedersen
- & Camilla Raiborg
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| Open Access
UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment
Characterising the tumour microenvironment features of lung adenocarcinoma (LUAD) remains crucial. Here, the authors perform single cell RNA sequencing data analysis of 117 LUAD samples and functional assays and highlight the immunosuppressive role of UPP1high tumour cells.
- Yin Li
- , Manling Jiang
- & Chunlai Lu
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| Open Access
Assessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy
HLA-I plays a key role in triggering an immune response and predicting immune checkpoint efficacy. Here the authors develop a method for quantifying HLA-I neoantigen presentation capacity by integrating HLA-I allele divergence and neoantigens numbers, termed HAPS, to describe how immune checkpoint response may be mediated by HLA.
- Jiefei Han
- , Yiting Dong
- & Zhijie Wang
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| Open Access
ANKRD1 is a mesenchymal-specific driver of cancer-associated fibroblast activation bridging androgen receptor loss to AP-1 activation
The transcriptional program controlling the activation of cancer-associated fibroblasts (CAFs) remains to be elucidated. Here, the authors identify ANKRD1 as a mesenchymal-specific driver of CAF activation under negative direct control of androgen receptor, triggering AP-1 transcription factor complex activation.
- Luigi Mazzeo
- , Soumitra Ghosh
- & G. Paolo Dotto
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Article
| Open Access
Neutral 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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| Open Access
Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity
Natural killer (NK) cells control tumor growth through direct cytotoxicity and recruitment of other leukocytes. Here, using photoconversion-based labeling to track the fate of NK cells in vivo, the authors demonstrate that loss of NK cell function occurs very rapidly following their entry into tumors, but can be reversed by IL-15 administration.
- Isaac Dean
- , Colin Y. C. Lee
- & David R. Withers
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| Open Access
A 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 Access
Macro 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 Access
The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
CD8 + T cells are central players in anti-tumour immunity. Here authors identify Cul5, a ubiquitin E3 ligase as an important inhibitor of CD8 + T cell anti-tumour cytotoxicity and persistence via involvement with both T cell receptor and cytokine-regulated central pathways.
- Xiaofeng Liao
- , Wenxue Li
- & Dianqing Wu
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Article
| Open Access
Mutant 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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| Open Access
Distinct 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
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Article
| Open Access
Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) represents a high-risk B-ALL subtype. Here the authors report that Th17 cells and IL-17A expression are elevated in Ph+ B-ALL patients and that targeting IL-17A enhances imatinib efficacy in preclinical models.
- Feng Wang
- , Yunxuan Li
- & Bing Cui
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Article
| Open Access
MAPS: pathologist-level cell type annotation from tissue images through machine learning
Current cell annotation methods using high-plex spatial proteomics data are resource intensive and demand iterative expert input. Here, the authors present MAPS (Machine learning for Analysis of Proteomics in Spatial biology), an approach that facilitates rapid and precise cell type identification with human-level accuracy from spatial proteomics data.
- Muhammad Shaban
- , Yunhao Bai
- & Faisal Mahmood
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| Open Access
FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity
Modulation of regulatory T cells (Treg) in the tumour environment is a potential avenue to bolster anti-tumor immunity. Here Liu et al show that perturbation of the negative feedback loop involving STAT1- IFITM3 influences anti-tumor immunity, and that IFITM3 or STAT1 deficiency resulting in the fragility of tumor-infiltrating Treg cells.
- Xinnan Liu
- , Weiqi Zhang
- & Bin Li
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| Open Access
Single-cell multi-omics analysis of human testicular germ cell tumor reveals its molecular features and microenvironment
The molecular features and tumour microenvironment (TME) in seminoma remain to be characterised. Here, the authors perform single cell multi-omics and spatial transcriptomics and identify key gene expression programmes, immune cell subtypes and potential therapeutic targets.
- Xiaojian Lu
- , Yanwei Luo
- & Jingtao Guo
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| Open Access
Pathway centric analysis for single-cell RNA-seq and spatial transcriptomics data with GSDensity
Clustering-based analysis has limited power in highly dynamic single-cell data, which is a common situation in tumour samples. Here, authors introduce GSDensity, enabling pathway-centric analysis for the direct integration of data with their domain knowledge.
- Qingnan Liang
- , Yuefan Huang
- & Ken Chen
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| Open Access
Single-cell spatial metabolomics with cell-type specific protein profiling for tissue systems biology
The authors developed a framework for joint protein-metabolite profiling at the single-cell level in human tissue combining targeted multiplexed protein imaging and untargeted spatial metabolomics in a single pipeline.
- Thomas Hu
- , Mayar Allam
- & Ahmet F. Coskun
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| Open Access
Deep learning of cell spatial organizations identifies clinically relevant insights in tissue images
Cell spatial organization in tissue provides essential insights into diseases. Here, the authors show Ceograph, a graph convolutional network, for the analysis of pathology images to predict patient outcomes, highlighting cellular markers to guide personalized treatments and enhance biological understanding.
- Shidan Wang
- , Ruichen Rong
- & Guanghua Xiao
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Article
| Open Access
Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses
Acral melanoma (AM) is a rare melanoma subtype with unique features, where lymph node metastasis is closely associated with clinical outcomes. Here, the authors use single-cell and spatial transcriptomics to analyse early dissemination, tumour microenvironment, and heterogeneity in AM, and infer metabolic shifts with therapeutic implications.
- Chuanyuan Wei
- , Wei Sun
- & Jianying Gu
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Article
| Open Access
Inhibiting stromal Class I HDACs curbs pancreatic cancer progression
The desmoplastic stroma constitutes part of the microenvironment in pancreatic ductal adenocarcinoma. Here the authors show that Class I HDACs regulate the pro-desmoplastic and pro-tumorigenic transcriptional programs to support stromal activation and tumour progression.
- Gaoyang Liang
- , Tae Gyu Oh
- & Ronald M. Evans
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Article
| Open Access
Secretory GFP reconstitution labeling of neighboring cells interrogates cell–cell interactions in metastatic niches
Methodologies to study the mechanisms of cell–cell interactions in metastatic niches remain scarce. Here, the authors develop a secretory GFP reconstitution-based system to tag tissue-resident cells neighboring on cancer cells within the metastatic niche.
- Misa Minegishi
- , Takahiro Kuchimaru
- & Satoshi Nishimura
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Article
| Open Access
Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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Article
| Open Access
Fragment-sequencing unveils local tissue microenvironments at single-cell resolution
Experimentally preserving tissue microenvironments remains challenging for single-cell sequencing methods. Here, the authors introduce fragment-sequencing, a method that can preserve three-dimensional microenvironments in single-cell RNA-seq, thus allowing the reconstruction of spatial tissue niches.
- Kristina Handler
- , Karsten Bach
- & Andreas E. Moor
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Article
| Open Access
Robust mapping of spatiotemporal trajectories and cell–cell interactions in healthy and diseased tissues
The integration of spatial, imaging, and sequencing information enables the mapping of cellular dynamics within a tissue. Here, authors show three algorithms in stLearn software to accurately reveal spatial trajectory, detect cell-cell interactions, and impute missing data.
- Duy Pham
- , Xiao Tan
- & Quan H. Nguyen
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Article
| Open Access
3D bioprinted multilayered cerebrovascular conduits to study cancer extravasation mechanism related with vascular geometry
Geometrical complexities of blood vessels alter biophysical behaviors of circulating tumor cells, influencing cancer metastasis. Here, the authors develop a 3D bioprinted in vitro brain blood vessel-on-a-chip to investigate continuities between vascular geometry and metastatic cancer development.
- Wonbin Park
- , Jae-Seong Lee
- & Dong-Woo Cho
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Article
| Open Access
ID1 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 Access
CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade
TAK-931 is a selective CDC7 inhibitor and can induce replication stress (RS)-mediated chromosomal instability with antitumoral activity. Here the authors show that TAK-931-induced RS generates aneuploid cells with an inflammatory phenotype, rendering tumors sensitive to immune-checkpoint blockade.
- Tomoko Yamamori Morita
- , Jie Yu
- & Akihiro Ohashi
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Article
| Open Access
Simultaneous selection of nanobodies for accessible epitopes on immune cells in the tumor microenvironment
INSPIREseq discovers accessible epitopes in complex environments and leads to nanobodies targeting thousands of epitopes. This in vivo diversity selection identifies selective nanobodies, potentially expediting target discovery and drug development.
- Thillai V. Sekar
- , Eslam A. Elghonaimy
- & Todd A. Aguilera
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Comment
| 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 Access
Cancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction
Cancer-associated fibroblasts (CAFs) can produce ECM and form a physical barrier around the tumour. Here, the authors show in transgenic mouse models and in vitro systems that CAFs are able to actively compress cancer cells using actomyosin contractility and this leads to a modulation of cancer cell mechanosensing and tumour reorganisation.
- Jorge Barbazan
- , Carlos Pérez-González
- & Danijela Matic Vignjevic
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Article
| Open Access
The 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 Access
Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy
Radiotherapy (RT) sensitizers have been used to overcome tumor hypoxia and improve response to RT. Here the authors design and characterize a pH and oxygen sensitive nano-molecular probe for imaging-guided cancer radiotherapy.
- Rong A
- , Haoyu Wang
- & Xilin Sun
Microenvironmental reorganization in brain tumors following radiotherapy and recurrence revealed by hyperplexed immunofluorescence imaging