Immunology
Abstract
Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non–small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.
Authors
Dijana Djureinovic, Björn M. Hallström, Masafumi Horie, Johanna Sofia Margareta Mattsson, Linnea La Fleur, Linn Fagerberg, Hans Brunnström, Cecilia Lindskog, Katrin Madjar, Jörg Rahnenführer, Simon Ekman, Elisabeth Ståhle, Hirsh Koyi, Eva Brandén, Karolina Edlund, Jan G. Hengstler, Mats Lambe, Akira Saito, Johan Botling, Fredrik Pontén, Mathias Uhlén, Patrick Micke
Abstract
BACKGROUND. Children treated with cerebrospinal fluid (CSF) shunts to manage hydrocephalus frequently develop shunt failure and/or infections, conditions that present with overlapping symptoms. The potential life-threatening nature of shunt infections requires rapid diagnosis; however, traditional microbiology is time consuming, expensive, and potentially unreliable. We set out to identify a biomarker that would identify shunt infection.
METHODS. CSF was assayed for the soluble membrane attack complex (sMAC) by ELISA in patients with suspected shunt failure or infection. CSF was obtained at the time of initial surgical intervention. Statistical analysis was performed to assess the diagnostic potential of sMAC in pyogenic-infected versus noninfected patients.
RESULTS. Children with pyogenic shunt infection had significantly increased sMAC levels compared with noninfected patients (3,211 ± 1,111 ng/ml vs. 26 ± 3.8 ng/ml,
CONCLUSION. Elevated CSF sMAC levels are both sensitive and specific for diagnosing pyogenic shunt infection and may serve as a useful prognostic biomarker during recovery from infection.
FUNDING. This work was supported in part by the Impact Fund of Children’s of Alabama.
Authors
Theresa N. Ramos, Anastasia A. Arynchyna, Tessa E. Blackburn, Scott R. Barnum, James M. Johnston
Abstract
Since 2011, over 300 human cases of infection, especially in exposed children, with the influenza A H3N2 variant (H3N2v) virus that circulates in swine in the US have been reported. The structural and genetic basis for the lack of protection against H3N2v induced by vaccines containing seasonal H3N2 antigens is poorly understood. We isolated 17 human monoclonal antibodies (mAbs) that neutralized H3N2v virus from subjects experimentally immunized with an H3N2v candidate vaccine. Six mAbs exhibited very potent neutralizing activity (IC50 < 200 ng/ml) against the H3N2v virus but not against current human H3N2 circulating strains. Fine epitope mapping and structural characterization of antigen-antibody complexes revealed that H3N2v specificity was attributable to amino acid polymorphisms in the 150-loop and the 190-helix antigenic sites on the hemagglutinin protein. H3N2v-specific antibodies also neutralized human H3N2 influenza strains naturally circulating between 1995 and 2005. These results reveal a high level of antigenic relatedness between the swine H3N2v virus and previously circulating human strains, consistent with the fact that early human H3 seasonal strains entered the porcine population in the 1990s and reentered the human population, where they had not been circulating, as H3N2v about a decade later. The data also explain the increased susceptibility to H3N2v viruses in young children, who lack prior exposure to human seasonal strains from the 1990s.
Authors
Sandhya Bangaru, Travis Nieusma, Nurgun Kose, Natalie J. Thornburg, Jessica A. Finn, Bryan S. Kaplan, Hannah G. King, Vidisha Singh, Rebecca M. Lampley, Gopal Sapparapu, Alberto Cisneros III, Kathryn M. Edwards, James C. Slaughter, Srilatha Edupuganti, Lilin Lai, Juergen A. Richt, Richard J. Webby, Andrew B. Ward, James E. Crowe Jr.
Abstract
Tregs imprint an early immunotolerant tumor environment that prevents effective antitumor immune responses. Using transcriptomics of tumor tissues, we identified early upregulation of VEGF and TGF-β pathways compatible with tolerance imprinting. Silencing of VEGF or TGF-β in tumor cells induced early and pleiotropic modulation of immune-related transcriptome signatures in tumor tissues. These were surprisingly similar for both silenced tumors and related to common downstream effects on Tregs. Silencing of VEGF or TGF-β resulted in dramatically delayed tumor growth, associated with decreased Tregs and myeloid-derived suppressor cells and increased effector T cell activation in tumor infiltrates. Strikingly, co-silencing of TGF-β and VEGF led to a substantial spontaneous tumor eradication rate and the combination of their respective inhibitory drugs was synergistic. VEGF and/or TGF-β silencing also restored tumor sensitivity to tumor-specific cell therapies and markedly improved the efficacy of anti–PD-1/anti–CTLA-4 treatment. Thus, TGF-β and VEGF cooperatively control the tolerant environment of tumors and are targets for improved cancer immunotherapies.
Authors
Tristan Courau, Djamel Nehar-Belaid, Laura Florez, Béatrice Levacher, Thomas Vazquez, Faustine Brimaud, Bertrand Bellier, David Klatzmann
Abstract
Airway and/or lung remodeling, involving exaggerated extracellular matrix (ECM) protein deposition, is a critical feature common to pulmonary diseases including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF). Fibulin-1 (Fbln1), an important ECM protein involved in matrix organization, may be involved in the pathogenesis of these diseases. We found that Fbln1 was increased in COPD patients and in cigarette smoke–induced (CS-induced) experimental COPD in mice. Genetic or therapeutic inhibition of
Authors
Gang Liu, Marion A. Cooley, Andrew G. Jarnicki, Alan C-Y. Hsu, Prema M. Nair, Tatt Jhong Haw, Michael Fricker, Shaan L. Gellatly, Richard Y. Kim, Mark D. Inman, Gavin Tjin, Peter A.B. Wark, Marjorie M. Walker, Jay C. Horvat, Brian G. Oliver, W. Scott Argraves, Darryl A. Knight, Janette K. Burgess, Philip M. Hansbro
Abstract
Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non–small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional
Authors
Grit S. Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y. Li, Kevin A. Buczkowski, Aaron K. Grant, Soumya Ullas, Kevin Rhee, Jillian D. Cavanaugh, Neermala Poudel Neupane, Camilla L. Christensen, Jan M. Herter, G. Mike Makrigiorgos, F. Stephen Hodi, Gordon J. Freeman, Glenn Dranoff, Peter S. Hammerman, Alec C. Kimmelman, Kwok-Kin Wong
Abstract
Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). Human
Authors
Hsing-Chuan Tsai, Yingxiang Huang, Christopher S. Garris, Monica A. Moreno, Christina W. Griffin, May H. Han
Abstract
In human myocarditis and its sequela dilated cardiomyopathy (DCM), the mechanisms and immune phenotype governing disease and subsequent heart failure are not known. Here, we identified a Th17 cell immunophenotype of human myocarditis/DCM with elevated CD4+IL17+ T cells and Th17-promoting cytokines IL-6, TGF-β, and IL-23 as well as GM-CSF–secreting CD4+ T cells. The Th17 phenotype was linked with the effects of cardiac myosin on CD14+ monocytes, TLR2, and heart failure. Persistent heart failure was associated with high percentages of IL-17–producing T cells and IL-17–promoting cytokines, and the myocarditis/DCM phenotype included significantly low percentages of FOXP3+ Tregs, which may contribute to disease severity. We demonstrate a potentially novel mechanism in human myocarditis/DCM in which TLR2 peptide ligands from human cardiac myosin stimulated exaggerated Th17-related cytokines including TGF-β, IL-6, and IL-23 from myocarditic CD14+ monocytes in vitro, and an anti-TLR2 antibody abrogated the cytokine response. Our translational study explains how an immune phenotype may be initiated by cardiac myosin TLR ligand stimulation of monocytes to generate Th17-promoting cytokines and development of pathogenic Th17 cells in human myocarditis and heart failure, and provides a rationale for targeting IL-17A as a therapeutic option.
Authors
Jennifer M. Myers, Leslie T. Cooper, David C. Kem, Stavros Stavrakis, Stanley D. Kosanke, Ethan M. Shevach, DeLisa Fairweather, Julie A. Stoner, Carol J. Cox, Madeleine W. Cunningham
Abstract
Conventional memory CD8+ T cells and mucosal-associated invariant T cells (MAIT cells) are found in blood, liver, and mucosal tissues and have similar effector potential following activation, specifically expression of IFN-γ and granzyme B. To better understand each subset’s unique contributions to immunity and pathology, we interrogated inflammation- and TCR-driven activation requirements using human memory CD8+ T and MAIT cells isolated from blood and mucosal tissue biopsies in ex vivo functional assays and single cell gene expression experiments. We found that MAIT cells had a robust IFN-γ and granzyme B response to inflammatory signals but limited responsiveness when stimulated directly via their TCR. Importantly, this is not due to an overall hyporesponsiveness to TCR signals. When delivered together, TCR and inflammatory signals synergize to elicit potent effector function in MAIT cells. This unique control of effector function allows MAIT cells to respond to the same TCR signal in a dichotomous and situation-specific manner. We propose that this could serve to prevent responses to antigen in noninflamed healthy mucosal tissue, while maintaining responsiveness and great sensitivity to inflammation-eliciting infections. We discuss the implications of these findings in context of inflammation-inducing damage to tissues such as BM transplant conditioning or HIV infection.
Authors
Chloe K. Slichter, Andrew McDavid, Hannah W. Miller, Greg Finak, Brenda J. Seymour, John P. McNevin, Gabriela Diaz, Julie L. Czartoski, M. Juliana McElrath, Raphael Gottardo, Martin Prlic
Abstract
Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA.
Authors
Maria Lucia L. Madariaga, Philip J. Spencer, Kumaran Shanmugarajah, Kerry A. Crisalli, David C. Chang, James F. Markmann, Nahel Elias, A. Benedict Cosimi, David H. Sachs, Tatsuo Kawai
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