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| Open AccessTertiary lymphoid structures critical for prognosis in endometrial cancer patients
Tertiary lymphoid structures (TLS) are associated with a reduced risk of cancer recurrence and improved response to immune checkpoint blockade in several tumor types. Here the authors identify L1CAM as a marker for mature TLS and show that the presence of TLS is associated with favorable prognosis in patients with endometrial cancer from the PORTEC-3 trial.
- Nanda Horeweg
- , Hagma H. Workel
- & Marco de Bruyn
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Article
| Open AccessT-cell dysfunction in the glioblastoma microenvironment is mediated by myeloid cells releasing interleukin-10
The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.
- Vidhya M. Ravi
- , Nicolas Neidert
- & Dieter Henrik Heiland
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| Open AccessLin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression
The establishment of a pre-metastatic niche is a key step preceding metastasis formation. Here the authors show that tumor-intrinsic Lin28B, a RNA-binding protein, has an essential role in the formation of an immune-suppressive pre-metastatic niche, promoting lung metastasis of breast cancer.
- Meiyan Qi
- , Yun Xia
- & Lixing Zhan
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Article
| Open AccessSingle-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer
The tumour microenvironment has not been fully characterised in high-grade serous ovarian cancers (HGSOC). Here, the authors use highly multiplexed imaging to analyse the HGSOC immune microenvironment at spatial and single-cell resolution, with clinically relevant findings for BRCA1/2-mutated tumours.
- I.-M. Launonen
- , N. Lyytikäinen
- & A. Färkkilä
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Article
| Open AccessPrimary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells
The understanding of the mechanisms underlying the ability of disseminated tumor cells (DTCs) to form metastasis is incomplete. Here, by using high-resolution intravital imaging of the murine lung to track the fate of breast-derived DTCs, the authors show that macrophages within the primary tumor induce a pro-dissemination and pro-dormancy phenotype in tumor cells, favouring their extravasation in the lung.
- Lucia Borriello
- , Anouchka Coste
- & David Entenberg
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| Open AccessMatrix mechanics regulates epithelial defence against cancer by tuning dynamic localization of filamin
Epithelial cells have the ability to competitively remove potentially cancerous cells from the tissue. Here the authors discover that pathological stiffening of extracellular matrix leads to the loss of this basic epithelial defence against cancer.
- Shilpa P. Pothapragada
- , Praver Gupta
- & Tamal Das
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Article
| Open AccessCancer cell-expressed BTNL2 facilitates tumour immune escape via engagement with IL-17A-producing γδ T cells
Cancer cells producing ligands for the immune checkpoint molecules PD-1 and CTLA-4 is an important mechanism of tumour immune resistance. Here authors show that BTNL2 expression on cancer cells generates a dysfunctional tumour immune microenvironment via promoting IL-17A-producing γδ T cells.
- Yanyun Du
- , Qianwen Peng
- & Chenhui Wang
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Article
| Open AccessYeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth
Components of the yeast cell wall, including but not limited to β-glucan, have been reported to act as danger signals and promote immune responses. Here the authors report the design and anti-tumor immune responses elicited by yeast cell wall-based nanoparticles in preclinical cancer models.
- Jialu Xu
- , Qingle Ma
- & Chao Wang
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Article
| Open AccessC/EBPB-dependent adaptation to palmitic acid promotes tumor formation in hormone receptor negative breast cancer
Obesity is linked to cancer risk in post-menopausal breast cancer. At the molecular level this is governed by cellular adaption to palmitic acid through epigenetic activation of a C/EBPB-dependent transcriptional network that drives tumor formation.
- Xiao-Zheng Liu
- , Anastasiia Rulina
- & Nils Halberg
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Article
| Open AccessSingle-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.
- Hanbing Song
- , Hannah N. W. Weinstein
- & Franklin W. Huang
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Article
| Open AccessIntegrated single-cell transcriptome analysis reveals heterogeneity of esophageal squamous cell carcinoma microenvironment
The microenvironment of oesophageal squamous cell carcinomas (ESCC) is heterogeneous and can strongly impact response to treatment. Here, the authors characterize the ESCC tumour microenvironment with single-cell RNA-seq, finding CST1 + myofibroblasts with potential biological and prognostic significance as well as immunosuppression signatures.
- Huy Q. Dinh
- , Feng Pan
- & En-Min Li
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Article
| Open AccessHeterocellular OSM-OSMR signalling reprograms fibroblasts to promote pancreatic cancer growth and metastasis
Cancer-associated fibroblasts (CAFs) are a major component of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDA). Here the authors report the importance of macrophage-derived Oncostatin M in reprogramming CAFs to drive a pro-tumorigenic environment in PDA.
- Brian Y. Lee
- , Elizabeth K. J. Hogg
- & Claus Jørgensen
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| Open AccessLive tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination
Intravital imaging reveals macrophage-driven de novo induction of cancer stem cells in vivo, and their dramatic enrichment on dissemination through TMEM doorways. These findings provide a mechanism for the validated ability of TMEM doorway density to be prognostic for distant recurrence of metastatic tumors in breast cancer patients.
- Ved P. Sharma
- , Binwu Tang
- & Maja H. Oktay
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Article
| Open AccessAcetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming
Lactic acidosis is a metabolic state that occurs in injured tissues. Here the authors show that macrophages, in order to remain functional in acidosis, reduce their mitochondrial mass by mitophagy and rely on autophagy for survival, with mitochondrial integrity retained using acetoacetate as alternative fuel.
- Clément Adam
- , Léa Paolini
- & Pascale Jeannin
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| Open AccessSubclone-specific microenvironmental impact and drug response in refractory multiple myeloma revealed by single‐cell transcriptomics
Relapsed/refractory multiple myeloma (RRMM) is characterized by a remarkable heterogeneity and high drug resistance. Here, the authors analyse RRMM samples by single-cell RNA-sequencing, revealing molecular features associated with high-risk chromosomal 1q-gain and changes in the tumor microenvironment.
- Stephan M. Tirier
- , Jan-Philipp Mallm
- & Karsten Rippe
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Article
| Open AccessHigh endogenous CCL2 expression promotes the aggressive phenotype of human inflammatory breast cancer
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poor prognosis. Here the authors report the characterization of a human IBC cell line recapitulating the clinical and histopathological features of the human disease, and implicating its high level of CCL2 in macrophage infiltration and tumor progression.
- Anita Rogic
- , Ila Pant
- & Stuart A. Aaronson
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Article
| Open AccessSingle-cell analysis of diverse immune phenotypes in malignant pleural effusion
Detailed immune cell subset identification in human lung (malignant pleural effusion) MPE is important for diagnosis and prognosis. Here the authors use single cell RNA sequencing to identify immune cell types within MPE and show differential gene expression compared to circulating immune cells in blood.
- Zhong-Yin Huang
- , Ming-Ming Shao
- & Huan-Zhong Shi
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Article
| Open AccessImmune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma
PD-1 blockade is effective for only a subset of patients with cutaneous T cell lymphomas. Here, the authors report a spatial biomarker that uses immune and cancer cell topography to predict response to PD-1 blockade in this disease.
- Darci Phillips
- , Magdalena Matusiak
- & Garry P. Nolan
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| Open AccessDeciphering cell lineage specification of human lung adenocarcinoma with single-cell RNA sequencing
The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.
- Zhoufeng Wang
- , Zhe Li
- & Weimin Li
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Article
| Open AccessPostpartum breast cancer has a distinct molecular profile that predicts poor outcomes
The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.
- Sonali Jindal
- , Nathan D. Pennock
- & Pepper Schedin
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Article
| Open AccessEndothelial deletion of SHP2 suppresses tumor angiogenesis and promotes vascular normalization
SHP2 regulates pro-angiogenic VEGF-VEGFR signalling, but its role in tumour angiogenesis is unclear. Here the authors show that endothelial cell-specific deletion of SHP2 impairs tumour growth and angiogenesis in syngeneic mouse models through ASK1-c-JunSOX7 signalling axis.
- Zhiyong Xu
- , Chunyi Guo
- & Hongqiang Cheng
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Article
| Open AccessSpatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface
During tumor progression, cancer cells contact different neighboring cell types, but it is unclear how these interactions affect cancer cell behavior. Here, the authors use spatially resolved transcriptomics and single-cell RNA-seq to study the role of cilia at the tumormicroenvironment interface.
- Miranda V. Hunter
- , Reuben Moncada
- & Richard M. White
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Article
| Open AccessRegulatory T cells promote cancer immune-escape through integrin αvβ8-mediated TGF-β activation
TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth.
- Alexandra Lainé
- , Ossama Labiad
- & Julien C. Marie
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| Open AccessMicroenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy
Cytotoxic chemotherapy rarely generates durable anti-tumor immune responses. Here the authors show that tumor microenvironment-derived IL-6 promotes resistance to doxorubicin by suppressing CD8 T cell anti-tumor immune responses in a preclinical model of B-cell acute lymphoblastic leukemia.
- Eric H. Bent
- , Luis R. Millán-Barea
- & Michael T. Hemann
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Article
| Open AccessLung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3
The formation of the pre-metastatic niche enables the colonisation of disseminated cancer cells in distant organs. Here, the authors show that Th2 cytokines induce Complement 3 production in lung mesenchymal stromal cells, which recruits neutrophils and promotes the formation neutrophil extracellular traps, facilitating breast cancer cell metastasis to the lungs.
- Zhiyuan Zheng
- , Ya-nan Li
- & Yufang Shi
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Article
| Open AccessBone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo
Bone marrow-derived mesenchymal stroma cells (MSCs) in myeloid neoplasia have been hypothesized to carry somatic mutations and contribute to pathogenesis. Here the authors analyse ex-vivo cultures and primary MSCs derived from patients with myelodysplastic syndromes, finding functional alterations but no evidence of clonal mutations.
- Johann-Christoph Jann
- , Maximilian Mossner
- & Daniel Nowak
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| Open AccessDysregulation of TFH-B-TRM lymphocyte cooperation is associated with unfavorable anti-PD-1 responses in EGFR-mutant lung cancer
EGFR mutant lung tumours do not respond favourably to immunotherapy. Here, using single cell sequencing, the authors find that tissue resident memory CD8+ T like cells are reduced in the immune landscape of EGFR mutant tumours in comparison to wild type tumours and the presence of these cells may predict response to immunotherapy.
- Jae-Won Cho
- , Seyeon Park
- & Hye Ryun Kim
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Article
| Open AccessHexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities
Pericyte-endothelial cells interaction defines tumor vasculature and has implications in tumorigenesis development and therapy efficacy. Here, the authors show that hexokinase 2- driven glycolysis activates ROCK1-MLC2 mediated contractility in pericytes leading to tumor blood vessel abnormality.
- Ya-Ming Meng
- , Xue Jiang
- & Ping-Pui Wong
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Article
| Open AccessAn oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma
Oncolytic herpes simplex virus-1 lyses cancer cells while increases their immunogenicity. Blocking the CD47 “don’t eat me” signal on cancer cells promotes their phagocytosis by macrophages. Authors here show that oncolytic viruses expressing anti-CD47 antibodies improve glioblastoma survival in mouse models.
- Bo Xu
- , Lei Tian
- & Jianhua Yu
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| Open AccessCharacterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry
The tumour microenvironment (TME) may change in response to cancer treatments such as KRAS G12C inhibition, with potential implications for combination therapies. Here, the authors provide an antibody panel and workflow for analysing the TME with imaging mass cytometry in pre-clinical mouse models.
- Febe van Maldegem
- , Karishma Valand
- & Julian Downward
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| Open AccessNext generation of tumor-activating type I IFN enhances anti-tumor immune responses to overcome therapy resistance
Several studies have demonstrated that IFN-I administration can boost anti-tumor immune response against solid tumors. Here, to overcome the limitations of systemic IFN-I therapy (side effects, short half-life), the authors design a masked IFN-I prodrug activatable by tumor-associated proteases, showing preserved anti-tumor activity but reduced toxicity.
- Xuezhi Cao
- , Yong Liang
- & Yang-Xin Fu
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Article
| Open AccessEnvironmental eustress modulates β-ARs/CCL2 axis to induce anti-tumor immunity and sensitize immunotherapy against liver cancer in mice
The impact of positive environment stimulations (eustress) on cancer biology remains poorly understood. Here the authors show that exposure to an environment enrichment stimulates anti-tumor immunity and reduces tumor growth in preclinical models of liver cancer.
- Chaobao Liu
- , Yang Yang
- & Hui Wang
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Article
| Open AccessBioengineered 3D models of human pancreatic cancer recapitulate in vivo tumour biology
Personalized cancer medicine currently lacks custom platforms that mimic the microenvironment of human tissues. Here, the authors show how self-assembled patient-derived models of pancreatic cancer recapitulate key biological features of the original tumours such as matrix composition and stemness.
- David Osuna de la Peña
- , Sara Maria David Trabulo
- & Daniela Loessner
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Article
| Open Access9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy
The molecular mechanisms of resistance to immune checkpoint therapy remain elusive. Here, the authors perform immunogenomic analysis of TCGA data and data from clinical trials for antiPD-1/PD-L1 therapy and highlight the association of 9p21 loss with a cold tumor microenvironment and resistance to therapy.
- Guangchun Han
- , Guoliang Yang
- & Linghua Wang
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| Open AccessProfiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy
Targeting the inhibitory receptors (IRs) LAG-3, TIM-3 and TIGIT is a promising immune-oncology approach and the identification of biomarkers of response is crucial. Here, the authors apply automated single-cell count for these IRs in human renal cell carcinoma and investigate the immunogenomic landscape of the disease.
- Kimiharu Takamatsu
- , Nobuyuki Tanaka
- & Mototsugu Oya
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| Open AccessAdipocytes disrupt the translational programme of acute lymphoblastic leukaemia to favour tumour survival and persistence
How the bone marrow microenvironment evolves during induction chemotherapy to facilitate acute lymphoblastic leukaemia (ALL) survival remains unclear. Here the authors show that adipocytes emergent during ALL therapy aid the survival of ALL cells through a restrictive effect on the ALL proteome.
- Q. Heydt
- , C. Xintaropoulou
- & B. Patel
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Article
| Open AccessTumour-targeted interleukin-12 and entinostat combination therapy improves cancer survival by reprogramming the tumour immune cell landscape
The immunocytokine NHS-IL12 is targeted to necrotic tumour areas to prompt an immune response. Authors show here in mouse colon and breast models that the combination of histone deacetylase inhibitor, Entinostat, and NHS-IL12 generates a tumour microenvironment that favours tumour resolution.
- Kristin C. Hicks
- , Paul L. Chariou
- & Sofia R. Gameiro
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Article
| Open AccessAdipose stem cell niche reprograms the colorectal cancer stem cell metastatic machinery
Obesity is a major risk factor for cancer related death. Here, the authors show that visceral adipose-derived factors promote vasculogenesis and metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming colorectal cancer cells into a highly metastatic phenotype.
- Simone Di Franco
- , Paola Bianca
- & Giorgio Stassi
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Article
| Open AccessSingle-cell evaluation reveals shifts in the tumor-immune niches that shape and maintain aggressive lesions in the breast
The classification of breast lesions as indolent or aggressive to tailor treatment is crucial. Here, the authors use single-cell transcriptomics and multiparametric imaging of a breast cancer mouse model, report distinct tumor-immune features for the two types of lesions, and suggest the role of IL-17 signaling in disease progression.
- Vidya C. Sinha
- , Amanda L. Rinkenbaugh
- & Helen Piwnica-Worms
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Article
| Open AccessUSP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade
The cancer cell-extrinsic roles of deubiquitinases are unclear. Here the authors show that deubiquitinase USP12 downregulation contributes to development of an immune-suppressive tumour microenvironment in KRAS-driven lung cancers and mechanistically this is through the insufficient deubiquitination of the NF-κB inhibitor, PPM1B.
- Zhaojuan Yang
- , Guiqin Xu
- & Yongzhong Liu
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Article
| Open AccessStromal induction of BRD4 phosphorylation Results in Chromatin Remodeling and BET inhibitor Resistance in Colorectal Cancer
BRD4 has a pro-tumorigenic role but non-cell-autonomous mechanisms of BRD4 activation need to be elucidated. Here the authors unravel a mechanism by which CAFs activate BRD4 and induce resistance to BET inhibitors in cancer cells through IL6/IL8 signaling.
- Wenyu Wang
- , Yen-An Tang
- & Qiang Yu
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Article
| Open AccessThe HIF target MAFF promotes tumor invasion and metastasis through IL11 and STAT3 signaling
Hypoxia plays a critical role in tumor progression including invasion and metastasis. Here, the authors screened several hypoxia inducible genes and identified the oncogenic role of MAFF in breast cancer metastasis and that it activates IL11/STAT3 pathway.
- Eui Jung Moon
- , Stephano S. Mello
- & Amato J. Giaccia
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Article
| Open AccessResolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1
The response to neoadjuvant immune checkpoint blockade (ICB) in patients with recurrent gliolastoma multiforme (GBM) has been challenging to interpret. Here the authors develop a tumor analysis framework that reveals molecular similarities between GBM and melanoma and unique patterns of immunosuppression in GBM indicating potential co-targets for neoadjuvant ICB.
- Yue Lu
- , Alphonsus H. C. Ng
- & James R. Heath
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Article
| Open AccessCo-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance
Platinum chemotherapy is standard of care in ovarian cancers but treatment resistance commonly develops. Here, the authors show that the extracellular microenvironment is modulated following chemotherapy and the changes in matrix proteins and stiffness alter the cell death response of tumour cells.
- Elina A. Pietilä
- , Jordi Gonzalez-Molina
- & Kaisa Lehti
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Article
| Open AccessTumor-associated hematopoietic stem and progenitor cells positively linked to glioblastoma progression
A deeper knowledge of the immune cell profile within the brain cancer tumor microenvironment (TM) could identify targets to improve immunotherapy efficacy. Here, in glioblastoma, the authors find haematopoietic stem and progenitor cells in the TM, which are associated with poor prognosis and increased immunosuppression.
- I-Na Lu
- , Celia Dobersalske
- & Igor Cima
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Article
| Open AccessSingle-cell RNA sequencing shows the immunosuppressive landscape and tumor heterogeneity of HBV-associated hepatocellular carcinoma
Different cells of the tumour microenvironment in HBV-associated human hepatocellular carcinoma (HCC) interact to promote tumour immunity. Here the authors use single cell RNA sequencing to identify TIGIT-NECTIN2 as a pathway by which tumour-associated macrophages reduce intratumour T cell activation.
- Daniel Wai-Hung Ho
- , Yu-Man Tsui
- & Irene Oi-Lin Ng
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Article
| Open AccessExtracellular mRNA transported to the nucleus exerts translation-independent function
Nonvesicular extracellular RNA (nex-RNA) that are not packed in extracellular vesicles is detected outside the cell, but it is poorly understood. Here the authors report that nex-RNA is captured by a zinc finger protein and transported to the nucleus to enhance antimetastatic characters of the cell.
- Takeshi Tomita
- , Masayoshi Kato
- & Sachie Hiratsuka
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Article
| Open AccessImpairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis
Endo180, a collagen binding receptor, is highly expressed in a subset of cancer-associated fibroblasts. The authors show, using knockout mice and 3D in vitro assays, that Endo180 depletion impairs tumour fibroblast contractility and viability resulting in reduced tumour growth and metastasis.
- Ute Jungwirth
- , Antoinette van Weverwijk
- & Clare M. Isacke
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Article
| Open AccessSuppression of tumor-associated neutrophils by lorlatinib attenuates pancreatic cancer growth and improves treatment with immune checkpoint blockade
Tumor associated neutrophils have been correlated with poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). Here the authors show that the tyrosine kinase inhibitor lorlatinib modulates neutrophil development and recruitment in the tumor microenvironment, attenuating PDAC progression in preclinical mouse models.
- Sebastian R. Nielsen
- , Jan E. Strøbech
- & Janine T. Erler