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| Open AccessC5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC), however resistance and recurrence are often observed. Here, in preclinical models of BRCA1/2 wild type and homologous recombination competent BC, the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance, suggesting targeting C5aR1 as a therapeutic option.
- Xi Li
- , Alfonso Poire
- & Gordon B. Mills
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Article
| Open AccessObesity-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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Article
| Open AccessTertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer
Intratumoral tertiary lymphoid structure (TLS) density has been associated with better prognosis in several cancer types. Here the authors provide a comprehensive characterization of TLSs in patients with high-grade serous ovarian carcinoma.
- Lenka Kasikova
- , Jana Rakova
- & Jitka Fucikova
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Article
| Open AccessReciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer
TP63 is a master regulator transcription factor in squamous cell carcinomas (SCCs). Here the authors report that TP63 suppresses IFNγ signaling in SCC tumors and that its inhibition is associated with enhanced anti-tumor immunity and response to anti-PD1.
- Yuan Jiang
- , Yueyuan Zheng
- & Yan-Yi Jiang
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Article
| Open AccessDendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors
Response to immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC) remains suboptimal, even for tumors with elevated tumor mutational burden. Here the authors generate a model of NSCLC with enhanced mutational load, showing that, while still resistant to ICIs, hypermutated tumors become sensitive to dendritic cell-targeted therapy.
- Lucía López
- , Luciano Gastón Morosi
- & Federica Benvenuti
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Article
| Open AccessMi-2β promotes immune evasion in melanoma by activating EZH2 methylation
Mi-2β is an enzyme of the chromodomain helicase DNA family with roles in chromatin assembly, genomic stability and gene repression. Here the authors report that Mi-2β promotes immune evasion by activating EZH2 methylation and that loss of Mi-2β or its inhibition promote anti-tumor immune responses in preclinical melanoma models.
- Cang Li
- , Zhengyu Wang
- & Rutao Cui
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Article
| Open AccessComparative transcriptomics coupled to developmental grading via transgenic zebrafish reporter strains identifies conserved features in neutrophil maturation
Maturation of innate immune cells is a graded stereotypic process which is often conserved across species. Here authors label distinct neutrophil leukocyte developmental stages via generating combinations of transgenic zebrafish reporter strains, followed by transcriptome analysis of different neutrophil maturation stages and comparison to the gene expression profile of developing neutrophils from humans and mice.
- Stefanie Kirchberger
- , Mohamed R. Shoeb
- & Martin Distel
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Article
| Open AccessHeat shock protein gp96 drives natural killer cell maturation and anti-tumor immunity by counteracting Trim28 to stabilize Eomes
Natural killer (NK) cell maturation and function are regulated by multiple transcription factors (TF), but detailed molecular insights are scarce. Here the authors show that a TF, Eomes, is important for NK cell responses and cancer surveillance, in which Eomes expression is regulated by gp96 and Trim28 via the ubiquitination and degradation pathways.
- Yuxiu Xu
- , Xin Li
- & Songdong Meng
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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 AccessMARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer
Detection of neoepitopes from tumours is time consuming and requires the integration of genomic and/or RNA sequencing expression data. Here, the authors propose a machine learning method to enable direct identification of additional, tumour-specific sequences using mass spectrometry through integration of de novo peptide sequencing scores, MHC class I binding prediction, and peptide retention time prediction.
- Hanqing Liao
- , Carolina Barra
- & Nicola Ternette
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Article
| Open AccessPharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1
PD-L1 expression on the surface of cancer cells is believed to contribute to tumor immune evasion via triggering the inhibitory T cell co-receptor, PD-1, resulting in decreased T cell cytotoxicity. Here authors show that OTUB2 regulates PD-L1 expression via inhibition of its ubiquitin-mediated degradation, and that OTUB2 inhibition increases T cell cytotoxicity directed against tumors.
- Wenfeng Ren
- , Zilong Xu
- & Ningshao Xia
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Article
| Open AccessA distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing
γδ T cells are known to recognize phosphoantigen in the context of butyrophilins (BTN), yet the molecular rules underlying this phenomenon are unclear. Here, the authors demonstrate that a distinct topology of B30.2 and IgV domains within BTN3A complexes promotes antigen sensing and that the juxtamembrane region controls BTN complex formation.
- Mohindar M. Karunakaran
- , Hariharan Subramanian
- & Thomas Herrmann
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Article
| Open AccessLet-7 enhances murine anti-tumor CD8 T cell responses by promoting memory and antagonizing terminal differentiation
Effective CD8+ T cell immunity requires the generation of a long-lived memory pool and the maintenance of a non-exhausted effector T cell pool. The implementation of immune checkpoint blockade can reduced levels of exhaustion but lacks the ability to support memory formation in the effector pool. Here the authors suggest a role for Let-7 in the enhancement of the anti-tumor CD8+ T cell response by supporting memory via modulation of metabolic and differentiation state.
- Alexandria C. Wells
- , Kaito A. Hioki
- & Leonid A. Pobezinsky
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Article
| Open AccessA synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs
3D scaffolds can be used to recapitulate key aspects of the microenvironment of primary tumors and metastatic organs. Here the authors use subcutaneous porous 3D scaffold implants as a tool to study the immune signals in the lungs of metastatic breast cancer, revealing multifaceted roles of neutrophils in regulating lung metastasis.
- Jing Wang
- , Ramon Ocadiz-Ruiz
- & Lonnie D. Shea
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Article
| Open AccessChemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity
Agonists of the cytosolic DNA-sensing STING pathway potently remodel the tumour immune microenvironment to support anti-tumour adaptive immunity, but at the expense of adverse systemic inflammation. Here authors exchange the STING agonist MSA-2 with its prodrugs that are suitable for nano-liposomal delivery and thus achieve increased efficiency and decreased toxicity.
- Xiaona Chen
- , Fanchao Meng
- & Hangxiang Wang
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Article
| Open AccessOncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma
Glioblastoma (GBM) cells are metabolically dependent on exogenous cholesterol uptake and targeting cholesterol metabolism has been proposed as a therapeutic option for GBM. Here the authors show that cholesterol promotes phagocytic dysfunction in tumor associated macrophages and they develop an Apo-A1 armed oncolytic adenovirus restoring anti-tumor immunity in GBM preclinical models.
- Wang Shiqun
- , Yan Wei
- & Wei Jiwu
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Article
| Open AccessLoss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons
The role of PHD finger protein 8 (PHF8) in anti-tumour immunity remains to be investigated. Here, the authors suggest PHF8 as an epigenetic checkpoint and show that targeting PHF8 induces a viral mimicry response enhancing anti-tumour immunity in colorectal cancer.
- Yanan Liu
- , Longmiao Hu
- & Xiufeng Pang
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Article
| Open AccessLysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Lysophosphatidic acid is known to increase in concentration in multiple cancer types. Here, the authors show it affects CD8 T cell metabolism, phenotype, and effector functions, and plasma concentrations appear predictive of response to immunotherapy.
- Jacqueline A. Turner
- , Malia A. Fredrickson
- & Raul M. Torres
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Article
| Open AccessPRMT1 mediated methylation of cGAS suppresses anti-tumor immunity
cGAS/STING mediated immunity is linked to the anti-tumor response, but how tumor-intrinsic cGAS signals are countered during tumorigenesis and immune evasion is poorly understood. Here the authors show PRMT1 suppresses the anti-tumor immune response via arginine methylation of cGAS.
- Jing Liu
- , Xia Bu
- & Wenyi Wei
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Article
| Open AccessTargeting 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 AccessExecutioner 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 AccessCDK4/6 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 AccessmTORC1 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 AccessMyelodysplastic 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 AccessTumor-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 AccessInhibiting 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
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Article
| Open AccessDNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response
Understanding the molecular mechanisms of cancer immunoediting could provide insight into resistance to immunotherapy. Here, DNA barcoding provides evidence of ongoing immunoediting during metastasis and treatment with anti-PD1 and anti-CTLA4, and identifies cancer cell clones with unique immune evasive phenotypes.
- Louise A. Baldwin
- , Nenad Bartonicek
- & Simon Junankar
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Article
| Open AccessReprogramming of myeloid cells and their progenitors in patients with non-medullary thyroid carcinoma
Myeloid cells contribute to the tumor microenvironment of thyroid cancers, but their functional relevance is lesser known. Here authors show that myeloid cells infiltrating non-medullary thyroid carcinomas upregulate their antigen presentation-related genes, release less cytokines and over-produce reactive oxygen species, with transcriptional changes already present in extra-tumoral myeloid cells.
- Katrin Rabold
- , Martijn Zoodsma
- & Romana T. Netea-Maier
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Article
| Open AccessInhibition of UBA6 by inosine augments tumour immunogenicity and responses
The metabolic environment of tumours has wide-ranging effects on the anti-tumour immune response and the outcome of immune therapy. Authors show here that the purine metabolite inosine enhances tumour immunogenicity and thus immune checkpoint blockade therapy response by inhibiting the ubiquitin-activating enzyme UBA6 in tumour cells.
- Lei Zhang
- , Li Jiang
- & Baokun He
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Article
| Open AccessCancer co-opts differentiation of B-cell precursors into macrophage-like cells
The tumour microenvironment has been shown to change the phenotypes and functionality of immune cells to enable tumour propagation. Here authors show that cancers can derail B cell development to give rise to macrophage-like cells, contributing to cancer progression and metastasis via disabling local T cell response.
- Chen Chen
- , Bongsoo Park
- & Arya Biragyn
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Article
| Open AccessscRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory
Gastric cancer can vary in tumour stage and immune cell involvement. Here the authors compare gene expression in immune cell types from the blood and the tumour site from GC patients using single cell and TCR sequencing and show that IL17+CD8+ T cells have a phenotype related to that seen with exhausted cells.
- Keyong Sun
- , Runda Xu
- & Xun Lan
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Article
| Open AccessCircular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands
Glioblastoma (GBM) is a highly aggressive brain tumor, frequently resistant to therapies, including natural killer (NK) cell based immunotherapy. Here, the authors show that the circular RNA EZH2 is highly expressed in GBM and encodes the peptide EZH2-92aa, whose expression is associated with inhibition of NK cell cytotoxicity.
- Jian Zhong
- , Xuesong Yang
- & Nu Zhang
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Article
| Open AccessBreast cancer cell-derived extracellular vesicles promote CD8+ T cell exhaustion via TGF-β type II receptor signaling
Understanding the factors that hamper immune therapy in breast cancer may increase the range of patients who benefit. Here authors show that breast cancer cells produce and subsequently transfer active TGF-β type II receptors to CD8 + T cells to render them exhausted, thus paralyzing the anti-tumor immune response.
- Feng Xie
- , Xiaoxue Zhou
- & Fangfang Zhou
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Article
| Open AccessMitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression
Cancer cells downregulate surface expression of major histocompatibility complex I (MHC-I) for immune evasion. Here, the authors show that rapid mitochondrial fission activates the ER-stress response leading to reduced MHC-I complex formation and cell surface expression in solid cancer cells; moreover inhibition of mitochondrial fission increases the immune-mediated anticancer response in murine models.
- Xinyuan Lei
- , Hsinyu Lin
- & Jinsong Li
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Article
| Open AccessRegulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Immune checkpoint blockade is a promising approach to treat lung cancer, however, immune related adverse events hold back success in some patients. Here authors show that regulatory B cells fail to limit self-reactive T cells in these patients, and B cell phenotyping prior treatment may identify those at risk for these unfavourable outcomes.
- Akshay J. Patel
- , Zena N. Willsmore
- & Gary W. Middleton
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Article
| Open AccessPeptide vaccine-treated, long-term surviving cancer patients harbor self-renewing tumor-specific CD8+ T cells
The success of peptide vaccine treatment in cancer relies on the build-up of an efficient cytotoxic T cell response against the tumour antigen. Authors show here that tumour-specific memory CD8 T cells are able to persist and possibly even proliferate in the peripheral blood of long-surviving hepatocellular carcinoma patients.
- Eishiro Mizukoshi
- , Hidetoshi Nakagawa
- & Shuichi Kaneko
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Article
| Open AccessTargeting TCTP sensitizes tumor to T cell-mediated therapy by reversing immune-refractory phenotypes
Translationally controlled tumor protein (TCTP) regulates several cellular processes, including apoptosis, and is overexpressed in several cancer types. Here, the authors report that high levels of TCTP are associated with poor response to anti-PD-L1 and that TCTP targeting increases the efficacy of T cell-mediated anti-tumor therapy.
- Hyo-Jung Lee
- , Kwon-Ho Song
- & Tae Woo Kim
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Article
| Open AccessNeoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma
Immune checkpoint blockade therapy is successful in a high proportion of cancer patients, but others remain unresponsive. Authors here show that therapeutic success might be predictable in metastatic bladder cancer by longitudinal analysis of the early neoantigen-specific CD8 T cell response in peripheral blood.
- Jeppe Sejerø Holm
- , Samuel A. Funt
- & Sine Reker Hadrup
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Article
| Open AccessTrajectory of immune evasion and cancer progression in hepatocellular carcinoma
In order to design cancer immune therapies, it is important to understand how tumours evade the immune response that is mounted against them. Authors here analyse the distribution and properties of immune cells in hepatocellular carcinoma and describe a progressive tumour-immune co-evolution programme from early to late stage cancer.
- Phuong H. D. Nguyen
- , Martin Wasser
- & Valerie Chew
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Article
| Open AccessCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
- Nekisa Zakeri
- , Andrew Hall
- & Mala K. Maini
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Article
| Open AccessEBV miRNAs BART11 and BART17-3p promote immune escape through the enhancer-mediated transcription of PD-L1
Epstein-Barr virus (EBV)-encoded latent genes are reported to regulate PD-L1 expression to promote immune escape. Here, the authors show that EBV-encoded miRNAs EBV-miR-BART11 and EBV-miR-BART17-3p upregulate PD-L1 expression in nasopharyngeal carcinoma and gastric cancer by targeting FOXP1 and PBRM1.
- Jie Wang
- , Junshang Ge
- & Zhaoyang Zeng
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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 AccessThe induction of peripheral trained immunity in the pancreas incites anti-tumor activity to control pancreatic cancer progression
The advent of immunotherapy has revolutionised cancer therapeutics, but its application in the context of pancreatic ductal adenocarcinoma has been limited. Here authors explore the effect of innate trained responses to fungal β-glucan and assess its effect in a murine model of pancreatic ductal adenocarcinoma where they observe reduced tumour burden and enhanced survival.
- Anne E. Geller
- , Rejeena Shrestha
- & Jun Yan
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Article
| Open AccessProgranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression
Immune responses to pancreatic ductal adenocarcinoma can be inhibited by cancer cells. Here the authors show that high levels of progranulin in PDAC inhibits immune responses by reducing MHC class I antigen presentation through enhanced degradation of MHC class I via autophagy.
- Phyllis F. Cheung
- , JiaJin Yang
- & Jens T. Siveke
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Article
| Open AccessProtein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response
Microsatellite instability (MSI), caused by deficiency of the DNA mismatch repair system, has been associated with improved response to immune checkpoint blockade (ICB). Here the authors show that inactivation of protein phosphatase 2A induces a MSI status, promoting cytotoxic T cell infiltration and response to ICB in pre-clinical cancer models.
- Yu-Ting Yen
- , May Chien
- & Shih-Chieh Hung
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Article
| Open AccessDepletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab
Elimination of regulatory T cells via the anti-CCR4 monoclonal antibody, mogamulizumab, is expected to augment anti-tumour immune response. Authors show here that although regulatory T cell targeting is successful, clinical improvement remains minimal in patients with solid tumours due to concomitant and unintended depletion of central memory CD8+ T cells.
- Yuka Maeda
- , Hisashi Wada
- & Hiroyoshi Nishikawa
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Article
| Open AccessAsthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Clinical studies have suggested a reduced incidence of brain tumors, including optic gliomas, in children with asthma. Here, in a mouse model of Neurofibromatosis type 1 associated low grade optic glioma, the authors show that experimental asthma induction decreases glioma formation and growth, resulting from T cell-dependent inhibition of microglia-mediated tumor support.
- Jit Chatterjee
- , Shilpa Sanapala
- & David H. Gutmann
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Article
| Open AccessTumor evolution selectively inactivates the core microRNA machinery for immune evasion
Dysregulation of the microRNA machinery has crucial roles in cancer development. Here the authors show that inactivation of proteins involved in microRNA-mediated gene silencing, such as ANKRD52 or AGO2, confers resistance to T cell-mediated immune response in a preclinical cancer model.
- Tian-Yu Song
- , Min Long
- & Yong Cang
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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