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MetaTiME integrates single-cell gene expression to characterize the meta-components of the tumor immune microenvironment
Integration and comparison of multiple single cell sequencing datasets can be used to compare different studies. Here the authors propose MetaTiME which compares the gene expression of single cells from the tumour microenvironment across different tumours and uses transportable labels and metacomponents to annotate cell types and states.
- Yi Zhang
- , Guanjue Xiang
- & Clifford A. Meyer
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Article
| Open Access
Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells
The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4+ T cells and that methionine supplementation promotes CD4+ T cell dependent anti-tumor immune responses.
- Mahesh Pandit
- , Yun-Seo Kil
- & Jae-Hoon Chang
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Article
| Open Access
Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer
The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.
- A. Gordon Robertson
- , Khyati Meghani
- & Joshua J. Meeks
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Article
| Open Access
Bridging clinic and wildlife care with AI-powered pan-species computational pathology
Artificial Intelligence (AI) has the potential of assisting the study and diagnosis of veterinary cancers. Here, the authors build a cancer digital pathology atlas encompassing multiple animal species and demonstrate an AI approach for comparative pathology, which yields insights about immune response and morphological similarities.
- Khalid AbdulJabbar
- , Simon P. Castillo
- & Yinyin Yuan
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Article
| Open Access
In silico cancer immunotherapy trials uncover the consequences of therapy-specific response patterns for clinical trial design and outcome
Conventional clinical trial design methods are not necessarily tailored for the unique characteristics of immunotherapies. Here the authors use late-stage in silico cancer immunotherapy trials to investigate how design decisions affect the trial outcome.
- Jeroen H. A. Creemers
- , Ankur Ankan
- & Johannes Textor
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Article
| Open Access
CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy
Neutrophil-mediated drug delivery has been investigated as a therapeutic approach for brain tumors. Here the authors report the anti-tumor activity of chlorotoxin-directed CAR neutrophils delivering chemodrug-loaded nanoparticles in preclinical glioblastoma models.
- Yun Chang
- , Xuechao Cai
- & Xiaoping Bao
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Article
| Open Access
Oncogenic drivers dictate immune control of acute myeloid leukemia
There is increasing evidence of a functional interaction between acute myeloid leukemia (AML) and immune cells, influencing disease outcome. Here the authors study how distinct oncogenes differentially affect the host immune response to leukemic cells in preclinical models of AML.
- Rebecca J. Austin
- , Jasmin Straube
- & Megan J. Bywater
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| Open Access
Priming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
It has been reported that inhibition of the epigenetic regulator DNA methyltransferase 1 (DNMT1) is associated with improved response to immune checkpoint blockade (ICB). Here the authors show that conditional deletion of Dnmt1 in endothelial cells is sufficient to promote T cell infiltration, reduce tumor growth and enhance ICB response in preclinical models.
- Dae Joong Kim
- , Swetha Anandh
- & Andrew C. Dudley
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Article
| Open Access
Targeting CXCL16 and STAT1 augments immune checkpoint blockade therapy in triple-negative breast cancer
Chemotherapy priming sensitizes triple-negative breast cancers to immune checkpoint blockade. However, immune suppressive myeloid cells may impede its optimal effect. Here authors characterise the immune suppressive myeloid cells via single-cell analyses of immune cells from low dose chemotherapy treated breast tumours and identify STAT1 signalling as a regulator for immune suppressive state.
- Bhavana Palakurthi
- , Shaneann R. Fross
- & Siyuan Zhang
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Article
| Open Access
Antimicrobial exposure is associated with decreased survival in triple-negative breast cancer
Here, in a cohort of 772 women undergoing triple-negative breast cancer (TNBC) therapy, the authors show that antimicrobial prescription during TNBC treatment associates with inferior overall and breast cancer-specific survival, in turn related to peripheral lymphocyte count and gut microbiome dysbiosis.
- Julia D. Ransohoff
- , Victor Ritter
- & Allison W. Kurian
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Article
| Open Access
Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice
IL-2 complexes (IL-2c) which are IL-2 complexed with anti-IL-2 can be used to promote T cell function. Here authors use IL2c in addition to checkpoint inhibitors and irradiation to increase anti-tumour T cell responses and promote tumour rejection in mouse cancer models.
- Kateryna Onyshchenko
- , Ren Luo
- & Gabriele Niedermann
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Article
| Open Access
Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy
Six transmembrane epithelial antigen of the prostate 1 (STEAP1) is a highly enriched cell surface antigen expressed in prostate cancer. Here the authors describe the design of STEAP1 directed CART cells and show their antitumor activity in preclinical models of prostate cancer, also in combination with a collagen binding domain-IL-12 fusion cytokine.
- Vipul Bhatia
- , Nikhil V. Kamat
- & John K. Lee
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Article
| Open Access
Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
Intratumoral abundance of chemokines, such as CXCL9, is an important driver of T cell infiltration in tumors. Here the authors describe the design of a tumor-specific expression strategy to drive secretion of CXCL9 and an anti-PD-L1 scFv (αPD-L1) in the tumor microenvironment, promoting T cell recruitment and anti-tumor immune response in preclinical cancer models.
- Yue Wang
- , Shi-Kun Zhou
- & Jun Wang
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Article
| Open Access
Localized nuclear reaction breaks boron drug capsules loaded with immune adjuvants for cancer immunotherapy
Boron neutron capture therapy (BNCT) is a type of radiotherapy that induces cell damage through a localized nuclear reaction. Here the authors describe the design of a carborane-based covalent organic framework as a boron capsule loaded with immune adjuvants for concurrent BNCT and immunotherapy, promoting anti-tumour immune responses in preclinical cancer models.
- Yaxin Shi
- , Zhibin Guo
- & Zhibo Liu
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Article
| Open Access
Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma
Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
- Zhihong Chen
- , Nishant Soni
- & Dolores Hambardzumyan
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Article
| Open Access
Single cell analysis in head and neck cancer reveals potential immune evasion mechanisms during early metastasis
The molecular mechanisms underlying lymph-node metastasis in head and neck squamous-cell carcinoma remain to be investigated. Here, the authors perform single-cell RNA sequencing of cancer cells and CD8 + T cells and suggest potential mechanisms of immune evasion during early metastasis.
- Hong Sheng Quah
- , Elaine Yiqun Cao
- & N. Gopalakrishna Iyer
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Article
| Open Access
Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade
Immunotherapies have shown limited efficacy in patients with glioma. Here, based on an in vivo kinome knockout CRISPR screen, the authors show that checkpoint kinase 2 promotes CD8 T cell immune evasion and that its depletion or inhibition improve survival and response to PD1/PDL1 blockade in preclinical glioma models.
- Crismita Dmello
- , Junfei Zhao
- & Adam M. Sonabend
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Article
| Open Access
Epigenetic state determines the in vivo efficacy of STING agonist therapy
STING agonists have shown limited efficacy in early-phase clinical trials despite promising pre-clinical data. This study shows the potential clinical relevance of the use of combination STING agonists and demethylating agent therapies to induce the expression of STING.
- Rana Falahat
- , Anders Berglund
- & James J. Mulé
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Article
| Open Access
Clonal dynamics of alloreactive T cells in kidney allograft rejection after anti-PD-1 therapy
Immune checkpoint inhibitors (ICI) may have unanticipated side effects in transplant recipients who subsequently develop tumors. Here the authors used single-cell sequencing to identify and characterize allogeneic reactive T cells that developed after an ICI course for melanoma in a transplant recipient.
- Garrett S. Dunlap
- , Daniel DiToro
- & Deepak A. Rao
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Article
| Open Access
Blocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression
The effect of β-glucans and their receptor Dectin-1 in tumor development remains controversial. Here the authors show that Dectin-1 signaling promotes the development of colorectal cancer (CRC) by inducing prostaglandin E2 production in myeloid-derived suppressor cells and by suppressing IL-22BP expression, suggesting dectin-1 blockade as a potential therapeutic target for CRC.
- Ce Tang
- , Haiyang Sun
- & Yoichiro Iwakura
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Article
| Open Access
Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis
The upstream metabolism of tryptophan has been described as a metabolic node in glioblastoma. Here the authors show that the downstream metabolism of tryptophan, resulting in the accumulation of quinolinate in glioblastoma, contributes to pro-tumorigenic immune suppressive activation of macrophages.
- Pravin Kesarwani
- , Shiva Kant
- & Prakash Chinnaiyan
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| Open Access
Integrated transcriptome study of the tumor microenvironment for treatment response prediction in male predominant hypopharyngeal carcinoma
Many patients with hypopharyngeal carcinoma (HPC) do not respond to first-line combination therapy. Here, the authors analyse the tumour and the tumour microenvironment of HPC patients treated with combination therapy using single-cell RNA-seq, and train a classifier to distinguish responders based on cell type composition.
- Yang Zhang
- , Gan Liu
- & Zhigang Huang
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Article
| Open Access
Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis
During apoptosis, mitochondrial outer membrane permeabilization results in cytosolic mitochondrial RNA (mtRNA). Here, the authors demonstrate that caspase-3/7 inhibition promotes a cytosolic mtRNA-driven Type I interferon response via MDA5/MAVS/IRF3, increasing the immunogenicity of chemotherapy-induced apoptosis.
- Shane T. Killarney
- , Rachel Washart
- & Kris C. Wood
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Article
| Open Access
CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy
LKB1 mutations have been associated with primary resistance to immune checkpoint inhibitors in patients with lung cancer. Here the authors show that Lkb1-deficient lung tumors are characterized by defective trafficking and adhesion of T cells and that, by upregulating ICAM1 expression, CDK4/6 inhibitors sensitize LKB1 mutant lung cancer to anti-PD1 blockade.
- Xue Bai
- , Ze-Qin Guo
- & Zhong-Yi Dong
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Article
| Open Access
mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion
B7-H3 is expressed at high levels in several cancer types and can suppress antitumor immune responses. Here the authors show that B7-H3 expression is dependent on mTORC1 activity and that inhibition of B7-H3 promotes antitumor immunity mediated by cytolytic CD4 + T cells in tumor models with mTORC1 hyperactivity.
- Heng-Jia Liu
- , Heng Du
- & Elizabeth P. Henske
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Article
| Open Access
Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response
Long noncoding RNA molecules are RNA transcripts long thought to remain untranslated. In this study, the authors demonstrate that certain lncRNA can be translated into peptides that are immunogenic to CD8+ T cells and promote anti-tumour responses when delivered as vaccine vectors in mice.
- Wojciech Barczak
- , Simon M. Carr
- & Nicholas B. La Thangue
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Comment
| Open AccessLarge-scale genomic analyses reveal alterations and mechanisms underlying clonal evolution and immune evasion in esophageal cancer
Esophageal cancers feature distinct manifestations between and within patients which complicate precision diagnosis, prognosis, and patient care. New genomic and epigenomic research uncovers novel mechanisms underlying both inter- and intra-tumoral heterogeneity in esophageal cancer, with significant biological and translational implications.
- De-Chen Lin
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Article
| Open Access
Tracking the evolution of esophageal squamous cell carcinoma under dynamic immune selection by multi-omics sequencing
It is essential to understand heterogeneity and evolution at different omics levels in oesophageal squamous cell carcinoma (ESCC). Here, the authors use multi-omics to analyse heterogeneity and evolution in ESCC patient samples, and characterise the levels of immune infiltration as well as selective pressure from the tumour microenvironment.
- Sijia Cui
- , Nicholas McGranahan
- & Shixiu Wu
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Article
| Open Access
TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models
The molecular mechanisms determining the response to radiotherapy remain incompletely understood. Here, the authors demonstrate that the E3 ubiquitin ligase and intracellular Fc receptor, TRIM21, impairs CD8+ T cell responses in nasopharyngeal carcinoma tumour models following ionizing radiation.
- Jun-Yan Li
- , Yin Zhao
- & Na Liu
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Article
| Open Access
FGL2-targeting T cells exhibit antitumor effects on glioblastoma and recruit tumor-specific brain-resident memory T cells
Glioblastoma is an aggressive type of cancer with poor patient prognosis. Here, the authors show that T cells armed with an FGL2-specific scFV can induce antitumour responses mediated by tissue-resident memory T cells in the brain.
- Qingnan Zhao
- , Jiemiao Hu
- & Shulin Li
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Article
| Open Access
Bile salt hydrolase in non-enterotoxigenic Bacteroides potentiates colorectal cancer
Non-enterotoxigenic Bacteroides fragilis (NTBF) is abundant in colorectal cancer (CRC) patients and in a high-fat diet (HFD)-induced CRC model. Here the authors show that bile salt hydrolase-expressing NTBF is enriched in CRC patients with overweight and promotes tumor growth in an HFD-induced CRC mouse model.
- Lulu Sun
- , Yi Zhang
- & Frank J. Gonzalez
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Article
| Open Access
Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation
Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.
- Maxime Boy
- , Valeria Bisio
- & Nicolas Dulphy
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Article
| Open Access
Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy
The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.
- Marcel P. Trefny
- , Nicole Kirchhammer
- & Alfred Zippelius
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Article
| Open Access
Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei
DNA damage-induced micronuclei are linked to downstream viral signalling through the cGAS pattern recognition receptor. Here, the authors identify features of micronuclei chromatin that determine cGAS-MN recruitment and associated pathway activation.
- Kate M. MacDonald
- , Shirony Nicholson-Puthenveedu
- & Shane M. Harding
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Article
| Open Access
IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells
IFN-γ is associated with the efficacy of anti-tumour immune responses, and both pro- and anti-tumour functions have been ascribed to this cytokine. Here, the authors demonstrate that IFN-γ signalling inhibits the maintenance of stem-like T cells, thereby impairing anti-tumour immune responses.
- Julie M. Mazet
- , Jagdish N. Mahale
- & Audrey Gérard
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Article
| Open Access
Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation
YTHDF1 is an m6A reader that binds to methylated RNA and facilitates translation. Here the authors show that tumor intrinsic YTHDF1 promotes tumorigenesis by regulating lysosomal proteolysis of MHC-I and that YTHDF1 targeting boosts anti-tumor immunity and response to immunotherapy in preclinical cancer models.
- Wanzun Lin
- , Li Chen
- & Jiade J. Lu
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Article
| Open Access
Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis
The induction of immunogenic cell death (ICD) can potentiate antitumour immunity. Here the authors show that USP18, a negative regulator of IFN signaling protects cancer cells from ICD by suppressing the expression of canonical and non-canonical IFN-stimulated genes.
- Kei-ichiro Arimoto
- , Sayuri Miyauchi
- & Dong-Er Zhang
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Article
| Open Access
Oncolytic Parapoxvirus induces Gasdermin E-mediated pyroptosis and activates antitumor immunity
Oncolytic viruses are able to target tumours and thought to induce apoptosis while remodelling the tumour immune microenvironment. Here authors show in an oncolytic parapoxvirus ovis model that pyroptosis, a highly immunogenic Gasdermin-E-dependent cell death mechanism, is the dominant cell death pathway during virotherapy.
- Jing Lin
- , Shihui Sun
- & Wenqi He
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Article
| Open Access
CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment
The presence of classical type 1 dendritic cells (cDC1) positively influences prognosis in cancer, but their intricate networking with the various T cell types found in the tumour microenvironment is not fully appreciated. Here the authors show that cDC1 encounter with CD4+ helper T-cells transforms their gene expression signature, and these “helped” dendritic cells enable the function of anti-tumour cytotoxic T-cells.
- Xin Lei
- , Indu Khatri
- & Yanling Xiao
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Article
| Open Access
A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer
T cell exhaustion in breast tumours remains to be fully characterised. Here, single cell transcriptomics and imaging mass cytometry analysis of luminal breast tumours with or without exhausted T cells suggests distinct patterns of PD-1 and CXCL13 expression in T cells, and of MHC-I, but not PD-L1, expression in tumour cells.
- Sandra Tietscher
- , Johanna Wagner
- & Bernd Bodenmiller
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Article
| Open Access
PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
Tsp-1 in the tumor microenvironment is known to suppress tumor growth and progression. Here the authors show that PRSS2 represses Tsp-1 by binding to lipoprotein receptor-related protein 1 and suggest targeting PRSS2 mediated Tsp-1 repression as a potential therapeutic strategy.
- Lufei Sui
- , Suming Wang
- & Randolph S. Watnick
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Article
| Open Access
Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy
Recently, strategies based on the integration of nanotechnology with microbial carriers have been proposed for cancer therapy. Here the authors report the design of an ultrasound-controlled CRISPR/Cas9 gene editing system for IDO1 silencing compounded with the probiotic Lactobacillus rhamnosus GG, showing the induction of anti-tumor immune responses in preclinical cancer models.
- Jifeng Yu
- , Bangguo Zhou
- & Huixiong Xu
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Article
| Open Access
Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma
The use of chimeric antigen receptor modified immune cell therapeutics has improved the treatment of a range of tumours. Here the authors explore a dual-target iPSC-derived NK cell product as a potential therapeutic for the treatment of multiple myeloma.
- Frank Cichocki
- , Ryan Bjordahl
- & Jeffrey S. Miller
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Article
| Open Access
Inflammation promotes resistance to immune checkpoint inhibitors in high microsatellite instability colorectal cancer
Inflammatory conditions often affect colorectal cancer patients, and their effect on their ongoing treatment is a pressing medical question. Here authors show that inflammation interferes with local anti-tumour immune response and inhibits response to immune checkpoint blockade therapy via immunosuppressive neutrophil leukocytes.
- Qiaoqi Sui
- , Xi Zhang
- & Pei-Rong Ding
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Article
| Open Access
Inflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes
IL6 expression in the bone marrow is associated with reduced survival in paediatric AML. Here, the authors used RNA-seq to identify treatment resistance-associated co-occurring inflammatory signalling in leukemic cells.
- Hamid Bolouri
- , Rhonda E. Ries
- & Soheil Meshinchi
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Article
| Open Access
Mutant RIG-I enhances cancer-related inflammation through activation of circRIG-I signaling
By recognizing double-stranded RNA, RIG-I is implicated in anti-viral immune responses, but also in cancer development and intestinal inflammation. Here the authors identify frameshift germline mutations of RIG-I, resulting in the generation of a circular RNA associated with increased susceptibility to colitis-associated colon cancer.
- Jia Song
- , Wei Zhao
- & Dan Lu
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Article
| Open Access
Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors
Neck dissection and/or elective nodal irradiation (ENI) are commonly performed in patients with head and neck squamous cell carcinoma (HNSCC) to minimize local and regional recurrence. However, here the authors show that ENI blunts the immune response to combined radiation and immunotherapy, increasing local and distant tumor growth in HNSCC preclinical models.
- Laurel B. Darragh
- , Jacob Gadwa
- & Sana D. Karam
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Article
| Open Access
Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation
Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses
- Chengyu Shi
- , Ying Wang
- & Aifu Lin
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Article
| Open Access
Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.
- Dhivya Sridaran
- , Surbhi Chouhan
- & Nupam P. Mahajan
Type I interferon response in astrocytes promotes brain metastasis by enhancing monocytic myeloid cell recruitment