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Tumour immunology

Hsiling Chiu, Preeti Trisal, Chad Bjorklund, Soraya Carrancio, Estela G Toraño, Carla Guarinos, Despoina Papazoglou, Patrick R Hagner, Asma Beldi-Ferchiou, Karin Tarte, Marie-Hélène Delfau-Larue, Franck Morschhauser, Alan G Ramsay, Anita K Gandhi
Chemotherapy plus rituximab has been the mainstay of treatment for follicular lymphoma (FL) for two decades but is associated with immunosuppression and relapse. In phase 2 studies, lenalidomide combined with rituximab (R2 ) has shown clinical synergy in front-line and relapsed/refractory FL. Here, we show that lenalidomide reactivated dysfunctional T and Natural Killer (NK) cells ex vivo from FL patients by enhancing proliferative capacity and T-helper cell type 1 (Th1) cytokine release. In combination with rituximab, lenalidomide improved antibody-dependent cellular cytotoxicity in sensitive and chemo-resistant FL cells, via a cereblon-dependent mechanism...
February 14, 2019: British Journal of Haematology
Marlena Godlewska, Paul J Banga
Thyroid peroxidase (TPO) is the key enzyme involved in thyroid hormone synthesis. Autoantibodies to TPO (TPOAbs) are a hallmark of autoimmune thyroid disease (AITD). Here, we highlight recent progress over several years in understanding TPO biochemistry and function in various pathologies. TPO undergoes complex post-translational modifications as a dimer in endoplasmic reticulum during secretory pathway to apical membrane of thyrocytes. In silico modelling of TPO dimer has provided new information into the two enzyme active site regions and autoantigenic determinants...
February 8, 2019: Biochimie
Henrique Lemos, Lei Huang, George C Prendergast, Andrew L Mellor
Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer...
January 29, 2019: Nature Reviews. Cancer
Ernest C Borden
Over the past decade, preclinical and clinical research have confirmed the essential role of interferons for effective host immunological responses to malignant cells. Type I interferons (IFNα and IFNβ) directly regulate transcription of >100 downstream genes, which results in a myriad of direct (on cancer cells) and indirect (through immune effector cells and vasculature) effects on the tumour. New insights into endogenous and exogenous activation of type I interferons in the tumour and its microenvironment have given impetus to drug discovery and patient evaluation of interferon-directed strategies...
January 24, 2019: Nature Reviews. Drug Discovery
Guido Giordano, Pietro Parcesepe, Mario Rosario D'Andrea, Luigi Coppola, Tania Di Raimo, Andrea Remo, Erminia Manfrin, Claudia Fiorini, Aldo Scarpa, Carla Azzurra Amoreo, Fabiana Conciatori, Michele Milella, Francesca Pia Caruso, Luigi Cerulo, Almudena Porras, Massimo Pancione
BACKGROUND: Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear. METHODS: We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies...
January 22, 2019: Journal of Experimental & Clinical Cancer Research: CR
Daniel Shae, Kyle W Becker, Plamen Christov, Dong Soo Yun, Abigail K R Lytton-Jean, Sema Sevimli, Manuel Ascano, Mark Kelley, Douglas B Johnson, Justin M Balko, John T Wilson
Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumour immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP)...
January 21, 2019: Nature Nanotechnology
Katarzyna Bednarska-Szczepaniak, Damian Krzyżanowski, Magdalena Klink, Marek Nowak
BACKGROUND: Adenosine released by cancer cells in high amounts in the tumour microenvironment is one of the main immunosuppressive agents responsible for the escape of cancer cells from immunological control. Blocking adenosine receptors with adenosine analogues and restoring immune cell activity is one of the methods considered to increase the effectiveness of anticancer therapy. However, their direct effects on cancer cell biology remain unclear. Here we determined the effect of adenosine analogues on the response of cisplatin-sensitive and cisplatin-resistant ovarian cancer cells to cisplatin treatment...
January 17, 2019: Anti-cancer Agents in Medicinal Chemistry
S Peters, P Clézardin, I Márquez-Rodas, D Niepel, C Gedye
Drug repurposing offers advantages over traditional drug development in terms of cost, speed and improved patient outcomes. The receptor activator of nuclear factor kappa B (RANK) ligand (RANKL) inhibitor denosumab is approved for the prevention of skeletal-related events in patients with advanced malignancies involving bone, including solid tumours and multiple myeloma. Following improved understanding of the role of RANK/RANKL in cancer biology, denosumab has already been repurposed as a treatment for giant cell tumour of bone...
January 17, 2019: Clinical & Translational Oncology
Vincent Alcazer, Paola Bonaventura, Laurie Tonon, Sandrine Wittmann, Christophe Caux, Stéphane Depil
First generations of cancer vaccines using shared tumour antigens have been associated with disappointing clinical results. However, the paradigm shift introduced by immune checkpoint inhibitors has led to a renewed interest on anti-tumoural vaccination based on mutation-associated neoantigens. First clinical results are encouraging with some signs of clinical activity associated with induction of a specific immune response. In advanced or metastatic diseases, vaccination may either enhance the response to Programmed cell death 1 (PD-1/-L1) antagonists by increasing the number of effectors within the tumour or induce an anti-tumoural T-cell response in immunologically 'cold' tumours...
February 2019: European Journal of Cancer
Guy-Anne Turgeon, Andrew Weickhardt, Arun A Azad, Benjamin Solomon, Shankar Siva
Radiotherapy is an effective treatment modality commonly used in efforts to cure many localised cancers and in the palliation of symptoms in metastatic cancers. Immunotherapy has revolutionised cancer care by increasing the disease control and overall survival of patients in several cancer types; however, the majority of patients do not respond to currently available therapies based on immune checkpoint inhibitors (ICIs). The benefit of those agents is limited to patients who have a pre-existing active immune microenvironment that can be reactivated by ICIs...
January 2019: Medical Journal of Australia
Tsuyoshi Hamada, Jonathan A Nowak, Danny A Milner, Mingyang Song, Shuji Ogino
Molecular pathological epidemiology (MPE) is an integrative transdisciplinary field that addresses heterogeneous effects of exogenous and endogenous factors (collectively termed "exposures"), including microorganisms, on disease occurrence and consequence utilising molecular pathological signatures of the disease. In parallel with the paradigm of precision medicine, findings from MPE research can provide aetiological insights into tailored strategies of disease prevention and treatment. Due to the availability of molecular pathological tests on tumours, the MPE approach has been utilised predominantly in research on cancers including breast, lung, prostate, and colorectal carcinomas...
January 11, 2019: Journal of Pathology
Anna C Wilkins, Emmanuel C Patin, Kevin J Harrington, Alan A Melcher
Historically, our understanding of the cytotoxicity of radiation has centred on tumour cell-autonomous mechanisms of cell death. Here, tumour cell death occurs when a threshold number of radiation-induced non-reparable double-stranded DNA breaks is exceeded. However, in recent years, the importance of immune mechanisms of cell death has been increasingly recognised, as well as the impact of radiotherapy on non-malignant cellular components of the tumour microenvironment. Conserved anti-viral pathways that detect foreign nucleic acid in the cytosol and drive downstream interferon responses via the cGAS/STING pathway are key components of the immune response to radiation-induced DNA damage...
January 10, 2019: Journal of Pathology
Qun Chen, Bo Han, Xiangqi Meng, Chunbin Duan, Changxiao Yang, Zhenyu Wu, Magafurov Dinislam, Shihong Zhao, Safin Shamil, Chuanlu Jiang, Jinquan Cai
Mutualistic and dynamic communication between tumour cells and the surrounding microenvironment accelerates the initiation, progression, chemoresistance and immune evasion of glioblastoma (GBM). However, the immunosuppressive mechanisms of GBM has not been thoroughly elucidated to date. We enrolled six microenvironmental signatures to identify glioma microenvironmental genes. The functional enrichment analysis such as ssGSEA, ESTIMATE algorithm, Gene Ontology, Pathway analysis is conducted to discover the potential function of microenvironmental genes...
January 7, 2019: International Journal of Cancer. Journal International du Cancer
S Yu, J Shen, S Lao, B Yang, C Wu
BACKGROUND: Chemokine receptors and their ligands play a prominent role in regulating leucocyte migration. In the local milieu of inflammation, a high concentration of chemokines can recruit different chemokine receptor-expressing lymphocytes. OBJECTIVE: To understand the distinct immunological functions of CXC chemokine receptor 3 (CXCR3+ ) and CC chemokine receptor 4 (CCR4+ ) cluster of differentiation 4 (CD4+ ) T-cells accumulated in human tuberculosis (TB) pleural fluid after tuberculous antigen stimulation...
December 1, 2018: International Journal of Tuberculosis and Lung Disease
Yann-Alexandre Vano, Audrey Simonaggio, Constance Thibault, Stéphane Oudard
Clear cell kidney cancer is a tumour type whose development and progression is driven by the HIF/VEGF angiogenesis pathway. Anti-angiogenic (AA) agents, particularly anti-VEGFR tyrosine kinase (TKI) inhibitors, have profoundly modified the prognosis of patients in the metastatic setting (mRCC) since their registration in 2006. At the same time, mTOR inhibitors have also brought significant benefit to patients. More recently, treatments restoring adaptive anti-tumor immunity, anti-program death 1 (anti-PD-1) checkpoint inhibitors (ICP), have in turn revolutionized the management of patients with mRCC...
December 2018: Bulletin du Cancer
Alexandra Pender, Robin L Jones, Seth Pollack
Immunotherapeutics are increasingly recognized as a key tool in the armamentarium against malignancy. The success of immune checkpoint-targeting drugs and adoptive cell therapy has refocused attention on the potential anti-cancer effect of eliciting a tumour-specific immunological response. Sarcomas are a rare and diverse group of tumours with a limited prognosis in advanced disease despite systemic therapeutics. Various vaccine strategies including peptide vaccines against cancer testis antigens, dendritic cell vaccines, and viral vectors have been trialled in sarcoma with growing evidence of efficacy...
December 20, 2018: Cancers
Concetta Schiano, Andrea Soricelli, Filomena de Nigris, Claudio Napoli
High-resolution imaging is the gold standard to measure the functional and biological features of bone lesions. Imaging markers have allowed the characterization both of tumour heterogeneity and metabolic data. Besides, ongoing studies are evaluating a combined use of "imaging markers", such as SUVs, MATV, TLG, ADC from PET and MRI techniques respectively, and several "biomarkers" spanning from chemokine immune-modulators, such as PD-1, RANK/RANKL, CXCR4/CXCL12 to transcription factors, such as TP53, RB1, MDM2, RUNX family, EZH2, YY1, MAD2...
December 20, 2018: Expert Review of Clinical Immunology
Derin B Keskin, Annabelle J Anandappa, Jing Sun, Itay Tirosh, Nathan D Mathewson, Shuqiang Li, Giacomo Oliveira, Anita Giobbie-Hurder, Kristen Felt, Evisa Gjini, Sachet A Shukla, Zhuting Hu, Letitia Li, Phuong M Le, Rosa L Allesøe, Alyssa R Richman, Monika S Kowalczyk, Sara Abdelrahman, Jack E Geduldig, Sarah Charbonneau, Kristine Pelton, J Bryan Iorgulescu, Liudmila Elagina, Wandi Zhang, Oriol Olive, Christine McCluskey, Lars R Olsen, Jonathan Stevens, William J Lane, Andres M Salazar, Heather Daley, Patrick Y Wen, E Antonio Chiocca, Maegan Harden, Niall J Lennon, Stacey Gabriel, Gad Getz, Eric S Lander, Aviv Regev, Jerome Ritz, Donna Neuberg, Scott J Rodig, Keith L Ligon, Mario L Suvà, Kai W Wucherpfennig, Nir Hacohen, Edward F Fritsch, Kenneth J Livak, Patrick A Ott, Catherine J Wu, David A Reardon
Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3 . Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6 , is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8 ...
December 19, 2018: Nature
Amreen Aslam, Noopur Gupta, Thirumurthy Velpandian, Seema Sen
We report a case of xeroderma pigmentosum (XP) with endothelial dysfunction where the analysis of tears revealed elevated levels of proinflammatory cytokines, even in the absence of active inflammation and neovascularisation of the ocular surface. Although the role of ultraviolet (UV) radiation-induced inflammation in the occurrence of ocular manifestations of XP is known, little is published on the molecular mechanisms and there are no reports quantifying the presence of inflammatory cytokines in the tears of patients with ocular involvement of XP...
November 28, 2018: BMJ Case Reports
Victor I Seledtsov, Galina V Seledtsova
We propose a novel immunotherapeutic paradigm that justifies application of several antibodies to various membrane-associated antigens to achieve a critical threshold density of immune complexes on the surface of cancer cells sufficient for triggering downstream cytolytic pathways. Indeed, some cancer-associated antigens (such as cancer/testis antigens) were found to be expressed on many cancer (but not normal) cells, with their baseline membrane expression levels being originally quite low for some of them, or even further down-regulated due to immune-driven cell selection...
November 6, 2018: Oncotarget
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