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| Open AccessSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
PARP inhibitor (PARPi) therapy has demonstrated only modest efficacy in advanced breast cancer with BRCA mutations. Here the authors show that, by suppressing PARPi-triggered DNA damage and reducing dsDNA production in BRCA1-deficient breast tumor cells, tumor associated macrophages contribute to PARPi resistance, that can be overcome by STING agonism.
- Qiwei Wang
- , Johann S. Bergholz
- & Jean J. Zhao
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Article
| Open AccessExtracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy
The pro-tumorigenic effects of vimentin have been attributed to intracellular functions in tumour cells so far. Here, the authors show that tumour endothelial cells can secrete vimentin as a pro-angiogenic factor and that targeting of vimentin can be used as an immunotherapeutic strategy.
- Judy R. van Beijnum
- , Elisabeth J. M. Huijbers
- & Arjan W. Griffioen
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Article
| Open AccessNanoparticle-enhanced radiotherapy synergizes with PD-L1 blockade to limit post-surgical cancer recurrence and metastasis
Tumor recurrence after surgical resection is associated with a poor clinical outcome. Here the authors design a manganese dioxide-based nanosystem to increase response to radio-immunotherapy by relieving tumor hypoxia and targeting myeloid cells, showing reduced post-surgical cancer recurrence and metastasis.
- Xin Guan
- , Liping Sun
- & Wenwen Yue
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Comment
| Open AccessThe use of single-cell multi-omics in immuno-oncology
Single-cell multi-omics (scMulti-omics) has brought transformative insights into immuno-oncology, demonstrating success in describing novel immune subsets and defining important regulators of antitumor immunity. Here, we give examples of how scMulti-omics has been used in specific tumor studies and discuss how this may develop in the future.
- Anjun Ma
- , Gang Xin
- & Qin Ma
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Article
| Open AccessThe immune checkpoint B7x expands tumor-infiltrating Tregs and promotes resistance to anti-CTLA-4 therapy
B7x is a B7-family ligand with suppressive effects on effector T cells. Here the authors show that tumor-expressed B7x promotes the conversion of conventional CD4+ T cells into regulatory T cells within the tumor microenvironment to promote immune evasion and resistance to anti-CTLA-4 therapy.
- Peter John
- , Marc C. Pulanco
- & Xingxing Zang
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Comment
| Open AccessT follicular helper and B cell crosstalk in tertiary lymphoid structures and cancer immunotherapy
Tumor-infiltrating lymphocytes (TILs) are critical in the elimination of cancer cells, a concept highlighted by recent advances in cancer immunotherapy. Significant evidence reveals that their organization in tertiary lymphoid structures together with specific subpopulation composition/balances stimulates cellular crosstalk and anti-tumor immunity in patients.
- Soizic Garaud
- , Marie-Caroline Dieu-Nosjean
- & Karen Willard-Gallo
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Article
| Open AccessTargeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration
Therapeutic options for non-small cell lung cancer patients with brain metastases are limited. Here the authors design B7-H3 targeting CAR-T cells engineered to express the chemokine receptor CCR2b, and show improved accumulation in the brain and enhanced anti-tumor activity in preclinical models of lung cancer brain metastases.
- Hongxia Li
- , Emily B. Harrison
- & Hongwei Du
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Article
| Open AccessRNA polymerase II pausing factor NELF in CD8+ T cells promotes antitumor immunity
Negative elongation factor B (NELFB) is one of the four subunits of the NELF complex that controls RNA polymerase II pausing. Here the authors show that, by associating with the key T cell transcription factor TCF1, NELFB is required for eliciting CD8 + T cell memory and anti-tumor immune responses.
- Bogang Wu
- , Xiaowen Zhang
- & Rong Li
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Article
| Open AccessDENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion
Several mechanisms have been associated with transcriptional and post-transcriptional regulation of PD-L1 in cancer. Here the authors show that a RNA binding protein, DENR, positively regulates the translation of JAK2 and induces PD-L1 expression in tumor cells, associated with immune evasion.
- Baiwen Chen
- , Jiajia Hu
- & Hua-Bing Li
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Article
| Open AccessChemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations
COX-2-mediated prostaglandin E2 (PGE2) release from dying cancer cells contributes to cytotoxic therapy resistance. Here the authors show that cytotoxic drugs induce PGE2 release only in cancer cells with basal COX-2 activity and that pharmacological COX-2 inhibition can boost the efficacy of the combination of chemotherapy and PD-1 blockade.
- Charlotte R. Bell
- , Victoria S. Pelly
- & Santiago Zelenay
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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 AccessData-driven learning how oncogenic gene expression locally alters heterocellular networks
While mechanistic models play increasing roles in immuno-oncology, hand network curation is current practice. Here the authors use a Bayesian data-driven approach to infer how expression of a secreted oncogene alters the cellular landscape within the tumor.
- David J. Klinke II
- , Audry Fernandez
- & Anika C. Pirkey
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Article
| Open AccessDistinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy
Arthritis is the most common rheumatic immune-related adverse event (irAE) occurring in cancer patients receiving immune checkpoint inhibitors. Here the authors study the immune landscape of blood and synovial fluid samples from patients with arthritis-irAE, reporting immunological differences and similarities with classic autoimmune arthritis.
- Sang T. Kim
- , Yanshuo Chu
- & Roza Nurieva
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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 AccessSingle-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia
T cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder involving clonally expanded T cell clones and is not fully understood. Here the authors show that the rest of the immune repertoire is interconnected with the T-LGLL clonotype(s) and is more mature, cytotoxic and clonally restricted than in other cancers and autoimmune disorders.
- Jani Huuhtanen
- , Dipabarna Bhattacharya
- & Satu Mustjoki
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Article
| Open AccessUbiquitin ligase STUB1 destabilizes IFNγ-receptor complex to suppress tumor IFNγ signaling
The IFNγ response pathway is associated with response to immunotherapy in cancer. Here the authors show that high levels of the IFNγ-receptor (IFNγ-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFNγ-R1/JAK1 expression in cancer cells.
- Georgi Apriamashvili
- , David W. Vredevoogd
- & Daniel S. Peeper
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Article
| Open AccessCHMP2A regulates tumor sensitivity to natural killer cell-mediated cytotoxicity
Genetic alteration can render tumor cells resistant to immune cell-mediated killing. Here based on a genome-wide CRISPR screening, the authors show that expression of CHMP2A confers tumor cell resistance to NK cell-mediated cytotoxicity, mechanistically involving CHMP2A-dependent regulation of extracellular vesicle secretion.
- Davide Bernareggi
- , Qi Xie
- & Dan S. Kaufman
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Article
| Open AccessDepletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment
Increased density of tumor associated macrophages has been correlated with tumor recurrence following surgery. Here the authors design an alginate-based hydrogel encapsulating anti-PD-1-conjugated platelets and nanoparticles loaded with the macrophage-depleting CSF-1R inhibitor pexidartinib, showing inhibition of post-surgery tumor recurrence in preclinical models.
- Zhaoting Li
- , Yingyue Ding
- & Quanyin Hu
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Article
| Open AccessImmunosuppressive niche engineering at the onset of human colorectal cancer
Integration of mathematical modeling, ecological analyses of patient biopsies, and neoantigen heterogeneity suggests recruitment of immunosuppressive cells is key to initializing transformation from adenoma to carcinoma in human colorectal cancer.
- Chandler D. Gatenbee
- , Ann-Marie Baker
- & Alexander R. A. Anderson
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Article
| Open AccessLoss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing
Pancreatic cancer is characterized by an immunosuppressive microenvironment, leading to immune evasion. Here, based on in vitro and in vivo CRISPR screens, the authors identify Rnf31 and Vps4b as drivers of immune escape, showing that loss of their function leads to an increase in T cell-mediated killing and reduced tumor growth in preclinical pancreatic cancer models.
- Nina Frey
- , Luigi Tortola
- & Gerald Schwank
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Article
| Open AccessPI3Kγ stimulates a high molecular weight form of myosin light chain kinase to promote myeloid cell adhesion and tumor inflammation
Myeloid cell recruitment during tumor inflammation depends on the VCAM-1 receptor integrin α4β1. Here the authors show that a high molecular weight form of myosin light chain kinase, MLCK210, is required for myeloid cell integrin α4β1 activation and adhesion and that MLCK210 inhibition reduces tumor growth and inflammation in preclinical cancer models.
- Michael C. Schmid
- , Sang Won Kang
- & Judith A. Varner
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Article
| Open AccessTargeting myeloid derived suppressor cells reverts immune suppression and sensitizes BRAF-mutant papillary thyroid cancer to MAPK inhibitors
BRAF-V600E mutation is common in patients with papillary thyroid carcinoma (PTC) and has been associated with an aggressive phenotype. Here the authors show that the mutation supports cancer progression by reactivating the developmental factor TBX3 and promoting the recruitment of myeloid derived suppressive cells.
- Peitao Zhang
- , Haixia Guan
- & Li Zhao
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Article
| Open AccessUltrasound-controllable engineered bacteria for cancer immunotherapy
Synthetic biology has enabled the design of strategies for bacteria-based cancer immunotherapy. Here the authors report the development of focused ultrasound-activatable therapeutic bacteria engineered to express anti-CTLA-4 and anti-PD-L1 nanobodies for cancer immunotherapy.
- Mohamad H. Abedi
- , Michael S. Yao
- & Mikhail G. Shapiro
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Article
| Open AccessThermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy
Nitric oxide exerts a multitude of physiological functions and has also been exploited for anticancer therapies. Here the authors report the design of a micelle-releasing thermosensitive hydrogel system for the concomitant locoregional and lymphatic delivery of a nitric oxide donor and an anti-CTLA4 antibody, showing anti-tumor immune responses in preclinical cancer models.
- Jihoon Kim
- , David M. Francis
- & Susan N. Thomas
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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 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 AccessSingle-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma
Cutaneous T cell lymphomas (CTCL) are still poorly characterised at the molecular and single-cell level. Here, the authors analyse CTCL patient samples using single-cell RNA-seq, TCR and whole-exome sequencing, revealing the molecular profiles of malignant T cells and their association with the microenvironment and clinical outcomes.
- Xiangjun Liu
- , Shanzhao Jin
- & Yang Wang
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Article
| Open AccessRe-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer
Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.
- Alok Kumar Singh
- , Monali Praharaj
- & Trinity J. Bivalacqua
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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 AccessSingle-cell analysis of human glioma and immune cells identifies S100A4 as an immunotherapy target
Glioblastoma (GBM) is an immune cold tumour that is refractory to immunotherapy. Here, the authors identify molecular phenotypes of immune-suppressive and -promoting myeloid cells in GBM through single cell RNA sequencing and propose S100A4 as a regulator of immune suppressive T and myeloid cells in GBM.
- Nourhan Abdelfattah
- , Parveen Kumar
- & Kyuson Yun
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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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Comment
| Open AccessImmune-related adverse events and the balancing act of immunotherapy
The benefit from immune checkpoint inhibitors is tempered by immunologic toxicities, which involve diverse organs, have varying biology, onset time, and severity. Herein, we identify important areas of controversy and open research questions in the field of immune-related toxicity.
- Michael Conroy
- & Jarushka Naidoo
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Article
| Open AccessAdvances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data
The deconvolution of cell types is challenging in spatially-resolved transcriptomics. Here, the authors present SpatialDecon, a method for the deconvolution and quantification of cell types in spatial transcriptomics data, and show how it can be used to analyse immune response heterogeneity in cancer.
- Patrick Danaher
- , Youngmi Kim
- & Joseph M. Beechem
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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 AccessGPR182 limits antitumor immunity via chemokine scavenging in mouse melanoma models
Immunologically cold tumours don’t respond to immune checkpoint blockade inhibition due to poor recruitment of anti-tumour T cells. Authors show here that melanoma-associated lymphatic endothelial cells express G Protein-Coupled Receptor 182 that scavenges CXCL9 and other chemokines necessary for T cell recruitment.
- Robert J. Torphy
- , Yi Sun
- & Yuwen Zhu
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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 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 AccessNeoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma
Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .
- Joris L. Vos
- , Joris B. W. Elbers
- & Charlotte L. Zuur
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Article
| Open AccessInvestigating immune and non-immune cell interactions in head and neck tumors by single-cell RNA sequencing
The tumor microenvironment (TME) has an important role in Head and Neck Squamous Cell Carcinoma (HNSCC) progression. Here, using single-cell RNA sequencing and multiplexed imaging, the authors report the cellular complexity of the TME in patients with HNSCC, exploring inflammatory status, stromal heterogeneity and immune checkpoint receptor-ligand interactions.
- Cornelius H. L. Kürten
- , Aditi Kulkarni
- & Robert L. Ferris
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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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Article
| Open AccessCD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Costimulation has been shown to be required for optimal activation of T cells and it could be delivered either in trans with respect to the source of CD3-TCR ligation or in cis on the same cell. Here the authors show that CD137 costimulation is more effective when delivered in cis to enhance T cell proliferation and activation.
- Itziar Otano
- , Arantza Azpilikueta
- & Ignacio Melero
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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 AccessBiomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy
Antibodies targeting OX40 or CD137, two T cell costimulatory receptors, have been shown to improve antitumor immunity. Here the authors design a phospholipid-derived nanoparticle to deliver OX40 or CD137 mRNA to T cells in vivo, improving efficacy of anti-OX40 and anti-CD137 antibody therapy in preclinical tumor models.
- Wenqing Li
- , Xinfu Zhang
- & Yizhou Dong
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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 AccessGrowth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma
Poorly differentiated hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis. Here the authors show that GDF1, a member of the TGF-β superfamily, is highly expressed in high-grade poorly differentiated HCC and is associated with tumor plasticity, and that GDF1-induced reexpression of cancer testis antigens could render tumors sensitive to immune checkpoint inhibition.
- Wei Cheng
- , Hao-Long Li
- & Ming Liu
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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