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H K Angell, J Lee, K-M Kim, K Kim, S-T Kim, S H Park, W K Kang, A Sharpe, J Ogden, A Davenport, D R Hodgson, J C Barrett, E Kilgour
This study investigates the association of PD-L1 expression and immune cell infiltrates and their impact on clinical outcome, in addition to their overlap with microsatellite instability (MSI), HER2 and ATM molecular subgroups of gastric cancer (GC). PD-L1 membrane expression on tumour cells (TC) and infiltrating immune cells (IC), CD3 + T-lymphocytes, CD8+ cytotoxic T-cells, ATM and HER2 were assessed by immunohistochemistry (IHC) in the ACRG (Asian Cancer Research Group) GC cohort (N = 380). EBV status was determined using in situ hybridization and MSI status was performed using PCR and MLH1 IHC...
2019: Oncoimmunology
Kavitha Yaddanapudi, Shuhan Meng, Aaron G Whitt, Numan Al Rayyan, Jamaal Richie, Allison Tu, John W Eaton, Chi Li
The antigenic similarity between embryos and tumors has raised the idea of using embryonic material as a preventative vaccine against neoplastic disease. Indeed, we have previously reported that a vaccine comprises allogeneic murine embryonic stem cells (ESCs) and murine fibroblasts expressing GM-CSF (to amplify immune responses) successfully blocks the outgrowth of an implantable cancer (Lewis lung carcinoma; LLC) and lung tumors generated in mice using a combination of a mutagen followed by chronic pulmonary inflammation...
2019: Oncoimmunology
Thijs T Wind, Mathilde Jalving, Jacco J de Haan, Elisabeth G E de Vries, Marcel A T M van Vugt, Dirk-Jan Reijngoud, Rozemarijn S van Rijn, John B A G Haanen, Christian U Blank, Geke A P Hospers, Rudolf S N Fehrmann
This study aimed to establish the number of expression-based molecular subclasses in cutaneous melanoma, identify their dominant biological pathways and evaluate their clinical relevance. To this end, consensus clustering was performed separately on two independent datasets (n = 405 and n = 473) composed of publicly available cutaneous melanoma expression profiles from previous studies. Four expression-based molecular subclasses were identified and labelled 'Oxidative phosphorylation', 'Oestrogen response/p53-pathway', 'Immune' and 'Cell cycle', based on their dominantly expressed biological pathways determined by gene set enrichment analysis...
2019: Oncoimmunology
Nadia Mensali, Amalie Grenov, Niladri Bhusan Pati, Pierre Dillard, Marit Renée Myhre, Gustav Gaudernack, Gunnar Kvalheim, Else Marit Inderberg, Oddmund Bakke, Sébastien Wälchli
Eradication of tumors by the immune system relies on the efficient activation of a T-cell response. For many years, the main focus of cancer immunotherapy has been on cytotoxic CD8 T-cell. However, stimulation of CD4 helper T cells is critical for the promotion and maintenance of immune memory, thus a good vaccine should evoke a two-dimensional T-cell response. The invariant chain (Ii) is required for the MHC class II heterodimer to be correctly guided through the cell, loaded with peptide, and expressed on the surface of antigen presenting cells (APC)...
2019: Oncoimmunology
Francesca R Mariotti, Stefania Petrini, Tiziano Ingegnere, Nicola Tumino, Francesca Besi, Francesca Scordamaglia, Enrico Munari, Silvia Pesce, Emanuela Marcenaro, Alessandro Moretta, Paola Vacca, Lorenzo Moretta
Under physiological conditions, PD-1/PD-L1 interactions regulate unwanted over-reactions of immune cells and contribute to maintain peripheral tolerance. However, in tumor microenvironment, this interaction may greatly compromise the immune-mediated anti-tumor activity. PD-1+ NK cells have been detected in high percentage in peripheral blood and ascitic fluid of ovarian carcinoma patients. To acquire information on PD-1 expression and physiology in human NK cells, we analyzed whether PD-1 mRNA and protein are present in resting, surface PD-1- , NK cells from healthy donors...
2019: Oncoimmunology
Scott D Brown, Robert A Holt
The self-immunopeptidome is the repertoire of all self-peptides that can be presented by the combination of MHC variants carried by an individual, defined by their HLA genotype. Each MHC variant presents a distinct set of self-peptides, and the number of peptides in a set is variable. Subjects carrying MHC variants that present fewer self-peptides should also present fewer mutated peptides, resulting in decreased immune pressure on tumor cells. To explore this, we predicted peptide-MHC binding values using all unique 8-11mer human peptides in the human proteome and all available HLA class I allelic variants, for a total of 134 billion unique peptide--MHC binding predictions...
2019: Oncoimmunology
Audrey Mohr, Marie Cumin, Cristina Bagacean, Pierre Pochard, Christelle Le Dantec, Sophie Hillion, Yves Renaudineau, Christian Berthou, Adrian Tempescul, Hussam Saad, Jacques-Olivier Pers, Anne Bordron, Christophe Jamin
Chronic lymphocytic leukemia (CLL) is associated with abnormal T-cell responses responsible for defective anti-tumor activities. Intriguingly, CLL B cells share phenotypical characteristics with regulatory B (Breg) cells suggesting that they might negatively control the T-cell activation and immune responses. We elaborated an in vitro co-culture system with T cells to evaluate the Breg capacities of CLL B cells following innate Toll-like receptor 9 (TLR9) engagement. We demonstrated that B cells from half of the patients exhibited regulatory capacities, whilst B cells from the remaining patients were unable to develop a Breg function...
2019: Oncoimmunology
Raffaella Fontana, Laura Raccosta, Lucrezia Rovati, Knut R Steffensen, Aida Paniccia, Tomas Jakobsson, Giulio Melloni, Alessandro Bandiera, Giorgia Mangili, Alice Bergamini, Daniela Maggioni, Claudio Doglioni, Roberto Crocchiolo, Marina Cella, Michela Mattioli, Cristina Battaglia, Marco Colonna, Vincenzo Russo
Dendritic cells (DCs) initiate adaptive immune responses after their migration to secondary lymphoid organs. The LXR ligands/oxysterols and the RXR ligand 9-cis Retinoic Acid (9-cis RA) were shown to dampen DC migration to lymphoid organs through the inhibition of CCR7 expression. We performed transcriptomics of DCs undergoing maturation in the presence of the LXR ligand 22R-Hydroxycholesterol (22R-HC). The analysis highlighted more than 1500 genes modulated by 22R-HC treatment, including the triggering receptor expressed on myeloid cells (TREM)-1, which was found markedly up-regulated...
2019: Oncoimmunology
Cédric Rossi, Pauline Gravelle, Emilie Decaup, Julie Bordenave, Mary Poupot, Marie Tosolini, Don-Marc Franchini, Camille Laurent, Renaud Morin, Jean-Michel Lagarde, Loïc Ysebaert, Laetitia Ligat, Christine Jean, Ariel Savina, Christian Klein, Alba Matas Céspedes, Patricia Perez-Galan, Jean-Jacques Fournié, Christine Bezombes
Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a 'high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1+ CD16+ TCRVγ9Vδ2 γδ T lymphocytes...
2019: Oncoimmunology
Mathias Vormehr, Katharina Reinhard, Renata Blatnik, Kathrin Josef, Jan David Beck, Nadja Salomon, Martin Suchan, Abderraouf Selmi, Fulvia Vascotto, Johannes Zerweck, Holger Wenschuh, Mustafa Diken, Sebastian Kreiter, Özlem Türeci, Angelika B Riemer, Ugur Sahin
Cancer-associated mutations, mostly single nucleotide variations, can act as neoepitopes and prime targets for effective anti-cancer T-cell immunity. T cells recognizing cancer mutations are critical for the clinical activity of immune checkpoint blockade (ICB) and they are potent vaccine antigens. High frequencies of mutation-specific T cells are rarely spontaneously induced. Hence, therapies that broaden the tumor specific T-cell response are of interest. Here, we analyzed neoepitope-specific CD8+ T-cell responses mounted either spontaneously or after immunotherapy regimens, which induce local tumor inflammation and cell death, in mice bearing tumors of the widely used colon carcinoma cell line CT26...
2019: Oncoimmunology
Jose M Ayuso, Regan Truttschel, Max M Gong, Mouhita Humayun, Maria Virumbrales-Munoz, Ross Vitek, Mildred Felder, Stephen D Gillies, Paul Sondel, Kari B Wisinski, Manish Patankar, David J Beebe, Melissa C Skala
Immunotherapies against solid tumors face additional challenges compared with hematological cancers. In solid tumors, immune cells and antibodies need to extravasate from vasculature, find the tumor, and migrate through a dense mass of cells. These multiple steps pose significant obstacles for solid tumor immunotherapy and their study has remained difficult using classic in vitro models based on Petri dishes. In this work, a microfluidic model has been developed to study natural killer cell response. The model includes a 3D breast cancer spheroid in a 3D extracellular matrix, and two flanking lumens lined with endothelial cells, replicating key structures and components during the immune response...
2019: Oncoimmunology
Razelle Kurzrock, Tamas Hickish, Lucjan Wyrwicz, Mark Saunders, Qian Wu, Michael Stecher, Prasant Mohanty, Charles A Dinarello, John Simard
Bermekimab is a true human monoclonal antibody that targets interleukin-1alpa (IL-1α), an inflammation-mediating alarmin. IL-1 receptor antagonist (IL-1Ra) is a natural molecule that blocks IL-1α activity by occupying the IL-1 receptor. The effect of endogenous IL-1Ra levels on the effectiveness of bermekimab is unknown. We investigated whether pre-treatment levels of circulating IL-1Ra, assessed by an enzyme-linked immunoassay, correlated with achievement of the primary outcome endpoint (effect on lean body mass and symptoms at week 8) in a Phase III study (2:1 randomization) of bermekimab versus placebo (each with best supportive care) in advanced colorectal cancer...
2019: Oncoimmunology
Kristina Iribarren, Aitziber Buque, Laura Mondragon, Wei Xie, Sarah Lévesque, Jonathan Pol, Laurence Zitvogel, Oliver Kepp, Guido Kroemer
The treatment of breast cancer largely depends on the utilization of immunogenic chemotherapeutics, which, as a common leitmotif, stimulate the exposure of calreticulin (CALR) on the surface of cancer cells, thereby facilitating their recognition by dendritic cells for the uptake of tumor-associated antigens and subsequent antigen cross-presentation to cytotoxic T cells. Breast cancer cells also express the calreticulin antagonist CD47, which inhibits tumor cell phagocytosis and consequently subverts anticancer immune responses...
2019: Oncoimmunology
Timm Hoeres, Elisabeth Holzmann, Manfred Smetak, Josef Birkmann, Martin Wilhelm
Gamma delta (γδ) T-cell based immunotherapy is a promising concept for the treatment of hematologic malignancies. Not only in vitro but also in early phase clinical trials, zoledronic acid (Zol) and interleukin-2 (IL-2) have been successfully used to activate human γδ T-cells and to induce clinical anti-tumor effects. Aiming to improve the effectiveness of future γδ T-cell based immunotherapies against leukemia, we analyzed the impact of programmed cell death protein 1 (PD-1) signaling, on the different phases of γδ T-cell activation, of proliferation, production of anti-tumor cytokines and cytotoxic function in vitro ...
2019: Oncoimmunology
Katia Lemdani, Nathalie Mignet, Vincent Boudy, Johanne Seguin, Edward Oujagir, Olivia Bawa, Frédérique Peschaud, Jean-François Emile, Claude Capron, Robert Malafosse
Radiofrequency ablation (RFA) of colorectal liver metastases activates a specific T-cell response that is ineffective in avoiding recurrence. Recently, local immunomodulation garnered interests as a way to improve the immune response. We were interested in improving the RFA immune response priming to propose a curative treatment of colorectal cancer (CRC) based on antitumor immunity. First, we demonstrated that the RFA did not increase the tumor infiltrating lymphocytes in secondary distant tumors of patients and in mice model and could not avoid relapse...
2019: Oncoimmunology
Amélie Boichard, Timothy V Pham, Huwate Yeerna, Aaron Goodman, Pablo Tamayo, Scott Lippman, Garrett M Framton, Igor F Tsigelny, Razelle Kurzrock
Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature of the neo-antigens driving those beneficial responses remains unclear. Here, we show that APOBEC-related mutagenesis - a mechanism at the crossroads between anti-viral immunity and endogenous nucleic acid editing - increases neo-peptide hydrophobicity (a feature of immunogenicity), as demonstrated by in silico computation and in the TCGA pan-cancer cohort, where APOBEC-related mutagenesis was also strongly associated with immune marker expression...
2019: Oncoimmunology
Elise Ramia, Anna Maria Chiaravalli, Farah Bou Nasser Eddine, Alessandra Tedeschi, Fausto Sessa, Roberto S Accolla, Greta Forlani
Hepatocellular carcinoma (HCC) is the second cause of death for cancer worldwide, justifying the urgent need for novel therapeutic approaches. Immunotherapeutic strategies based on triggering and/or rescuing tumor antigen-specific T cells may be promising particularly if combined together. As preliminary step toward this goal, we have investigated the expression of antigen presenting molecules (HLA class I and class II) and immune checkpoints (PD-1 and PD-L1) in 43 HCC samples from distinct patients and in HCC cell lines...
2019: Oncoimmunology
Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Meijing Wu, Denise M Scholtens, Rohan Savoor, Bin Zhang, Jennifer D Wu, Craig Horbinski, Rimas V Lukas, David C Binder, Derek A Wainwright
Preclinical modeling and gene expression analyses have yielded distinct observations for the role of immune checkpoint, IDO1, in glioblastoma (GBM). Accordingly, our recent work differs with Garg et al . (2017) with respect to IDO1 among preclinical and bioinformatic GBM datasets. Here, we discuss the methodological differences that affected study interpretation, and potentially, future clinical decision-making for IDO1-targeting approaches against GBM.
2019: Oncoimmunology
Ann Hanna, Brandon J Metge, Sarah K Bailey, Dongquan Chen, Darshan S Chandrashekar, Sooryanarayana Varambally, Rajeev S Samant, Lalita A Shevde
Host responses to tumor cells include tumor suppressing or promoting mechanisms. We sought to detail the effect of Hedgehog (Hh) pathway inhibition on the composition of the mammary tumor immune portfolio. We hypothesized that Hh signaling mediates a crosstalk between breast cancer cells and macrophages that dictates alternative polarization of macrophages and consequently supports a tumor-promoting microenvironment. We used an immunocompetent, syngeneic mouse mammary cancer model to inhibit Hh signaling with the pharmacological inhibitor, Vismodegib...
2019: Oncoimmunology
Ahdab Alsaieedi, Angelika Holler, Pedro Velica, Gavin Bendle, Hans J Stauss
We explored whether engineering of T cell specificity and effector function improves immunotherapy of solid tumors. Although IL-12 can enhance cancer immunity, a strategy of safe IL-12 delivery without toxicity is currently lacking. We engineered T cells to express IL-12 controlled by the NFAT promoter responsive to TCR stimulation, or by the Tet-On promoter responsive to doxycycline. In vivo , NFAT-engineered T cells caused lethal toxicity, while Tet-engineered T cells were safe in the absence of doxycycline...
2019: Oncoimmunology
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