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Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130426.
Abstract
The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4– counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespectively of the tumor type.
Authors
Giorgia Alvisi, Jolanda Brummelman, Simone Puccio, Emilia Maria Cristina Mazza, Elisa Paoluzzi Tomada, Agnese Losurdo, Veronica Zanon, Clelia Peano, Federico S. Colombo, Alice Scarpa, Marco Alloisio, Ajithkumar Vasanthakumar, Rahul Roychoudhuri, Marinos Kallikourdis, Massimiliano Pagani, Egesta Lopci, Pierluigi Novellis, Jonas Blume, Axel Kallies, Giulia Veronesi, Enrico Lugli
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134622.
Abstract
Mycobacterium tuberculosis (Mtb) has co-evolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identifying the full complement by which host immunity is inhibited. Perturbing host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, LCMV and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of TB patients and their asymptomatic household contacts demonstrating that TB patients have DNA hyper-methylation of the IL-2-STAT5, TNF-NF-ϰB and IFN-γ signaling pathways. By MSRE-qPCR, multiple genes of the IL-12-IFN-γ signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1 and JAK2) were hyper-methylated in TB patients. The DNA hyper-methylation of these pathways is associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-γ, TNF, IL-6, CXCL9, CXCL10 and IL-1β production. The DNA hyper-methylation of the IL-12-IFN-γ pathway was associated with decreased IFN-γ induced gene expression and decreased IL-12 inducible up-regulation of IFN-γ. This work demonstrates that immune cells from TB patients are characterized by DNA hyper-methylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and non-specific immune responsiveness.
Authors
Andrew DiNardo, Kimal Rajapakshe, Tomoki Nishiguchi, Godwin Mtetwa, Sandra L. Grimm, Qiniso Dlamini, Jaquiline Kahari, Sanjana Mahapatra, Alexander W. Kay, Gugu Maphalala, Emily M. Mace, George Makedonas, Jeffrey D. Cirillo, Mihai Netea, Reinout van Crevel, Cristian Coarfa, Anna M. Mandalakas
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI132583.
Abstract
The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low tissue-resident CD8+ and CD4+ T-cell density (TRM) are unknown. We analyzed shedding episodes during chronic HSV-2 infection: viral clearance always predominated within 24 hours of detection even if viral load exceeded 107 HSV DNA copies; surges in granzyme B and interferon-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of TRM in situ proliferation, trafficking, cytolytic effects and cytokine alarm signaling from murine studies with viral kinetics, histopathology and lesion size data from humans. A sufficiently high density of HSV-2 specific TRM predicted rapid elimination of infected cells, but our data suggest that such TRM densities are relatively uncommon in infected tissues. At lower, more commonly observed TRM densities, TRM must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.
Authors
Pavitra Roychoudhury, David A. Swan, Elizabeth R. Duke, Lawrence Corey, Jia Zhu, Veronica A. Davé, Laura E. Richert-Spuhler, Jennifer M. Lund, Martin Prlic, Joshua T. Schiffer
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133753.
Abstract
Salt inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and heart failure pathogenesis remains unknown. Here, we showed that loss of SIK1 kinase activity protected against adverse cardiac remodeling and heart failure pathogenesis in rodent models and human iPSC-derived cardiomyocytes. We found that SIK1 phosphorylated and stabilized histone deacetylase 7 (HDAC7) protein during cardiac stress, an event that is required for pathologic cardiomyocyte remodeling. Gain- and loss-of-function studies of HDAC7 in cultured cardiomyocytes implicated HDAC7 as a pro-hypertrophic signaling effector that can induce c-Myc expression, indicating a functional departure from the canonical MEF2 co-repressor function of class IIa HDACs. Taken together, our findings reveal what we believe to be a previously unrecognized role for a SIK1-HDAC7 axis in regulating cardiac stress responses and implicate this pathway as a potential target in human heart failure.
Authors
Austin Hsu, Qiming Duan, Sarah McMahon, Yu Huang, Sarah A.B. Wood, Nathanael S. Gray, Biao Wang, Benoit G. Bruneau, Saptarsi M. Haldar
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI128073.
Abstract
De novo lipogenesis is tightly regulated by insulin and nutritional signals to maintain metabolic homeostasis; excessive lipogenesis induces lipotoxicity, leading to nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. Genetic lipogenic programs have been extensively investigated, but epigenetic regulation of lipogenesis is poorly understood. Here, we identified Slug as an important epigenetic regulator of lipogenesis. Hepatic Slug levels were markedly upregulated in mice by either feeding or insulin treatment. In primary hepatocytes, insulin stimulation increased Slug expression, stability, and interactions with epigenetic enzyme lysine-specific demethylase-1 (Lsd1). Slug bound to the fatty acid synthase (Fasn) promoter where Slug-associated Lsd1 catalyzed H3K9 demethylation, thereby stimulating Fasn expression and lipogenesis. Ablation of Slug blunted insulin-stimulated lipogenesis; conversely, overexpression of Slug, but not a Lsd1 binding-defective Slug mutant, stimulated Fasn expression and lipogenesis. Lsd1 inhibitor treatment also blocked Slug-stimulated lipogenesis. Remarkably, hepatocyte-specific deletion of Slug inhibited the hepatic lipogenic program and protected against obesity-associated NAFLD, insulin resistance, and glucose intolerance in mice. Conversely, liver-restricted overexpression of Slug, but not the Lsd1 binding-defective Slug mutant, had the opposite effects. These results unveil an insulin/Slug/Lsd1/H3K9 demethylation lipogenic pathway that promotes NAFLD and type 2 diabetes.
Authors
Yan Liu, Haiyan Lin, Lin Jiang, Qingsen Shang, Lei Yin, Jiandie D. Lin, Wen-Shu Wu, Liangyou Rui
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133572.
Abstract
Given the numerous health benefits of exercise, understanding how exercise capacity is regulated is a question of paramount importance. Circulating interleukin-6 (IL-6) levels surge during exercise and IL-6 favors exercise capacity. However, neither the cellular origin of circulating IL-6 during exercise nor the means by which this cytokine enhances exercise capacity have been formally established yet. Here we show through genetic means that the majority of circulating IL-6 detectable during exercise originates from muscle and that to increase exercise capacity, IL-6 must signal in osteoblasts to favor osteoclast differentiation and the release of bioactive osteocalcin in the general circulation. This explains why mice lacking the IL-6 receptor only in osteoblasts exhibit a deficit in exercise capacity of similar severity to the one seen in mice lacking muscle-derived IL-6 (mIL-6), and why this deficit is correctable by osteocalcin but not by IL-6. Furthermore, in agreement with the notion that IL-6 acts through osteocalcin, we demonstrate that mIL-6 promotes nutrient uptake and catabolism into myofibers during exercise in an osteocalcin-dependent manner. Lastly, we show that the crosstalk between osteocalcin and IL-6 is conserved between rodents and humans. This study provides evidence that a muscle-bone-muscle endocrine axis is necessary to increase muscle function during exercise in rodents and humans.
Authors
Subrata Chowdhury, Logan C Schulz, Biagio Palmisano, Parminder Singh, Julian Meyer Berger, Vijay K. Yadav, Paula Mera, Helga Ellingsgaard, Juan Hidalgo, Jens C. Brüning, Gerard Karsenty
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133215.
Abstract
Chimeric antigen receptor (CAR) T cell therapies can eliminate relapsed and refractory tumors, but the durability of anti-tumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, as well as influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and substituting this asparagine to phenylalanine (CD28-YMFM) promoted durable anti-tumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing towards Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and anti-tumor activity. This finding suggests modifications to the co-stimulatory domains of CAR-T cells can enable longer persistence and thereby improve anti-tumor response.
Authors
Sonia Guedan, Aviv Madar, Victoria Casado-Medrano, Carolyn E. Shaw, Anna Wing, Fang Liu, Regina M. Young, Carl H. June, Avery D. Posey Jr.
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134066.
Abstract
Chronic pancreatitis (CP) is considered an irreversible fibroinflammatory pancreatic disease. Despite numerous animal model studies, questions remain about local immune characteristics in human CP. We profiled pancreatic immune cell characteristics in control organ donors and CP patients that included hereditary and idiopathic CP undergoing total pancreatectomy with islet auto-transplantation. Flow cytometric analysis revealed a significant increase in the frequency of CD68+ macrophages in idiopathic CP. In contrast, hereditary CP showed a significant increase in CD3+ T cell frequency, which prompted us to investigate the T cell receptor β (TCRβ) repertoire in CP and controls. TCRβ-sequencing revealed a significant increase in TCRβ repertoire diversity and reduced clonality in both CP groups versus controls. Interestingly, we observed differences in Vβ-Jβ gene family usage between hereditary and idiopathic CP and a positive correlation of TCRβ rearrangements with disease severity scores. Immunophenotyping analyses in hereditary and idiopathic CP pancreata indicate differences in innate and adaptive immune responses, which highlights differences in immunopathogenic mechanism of disease among subtypes of CP. TCR repertoire analysis further suggests a role for specific T cell responses in hereditary versus idiopathic CP pathogenesis providing new insights into immune responses associated with human CP.
Authors
Bomi Lee, Julia Z. Adamska, Hong Namkoong, Melena D. Bellin, Joshua J. Wilhelm, Gregory L. Szot, David M. Louis, Mark M. Davis, Stephen Pandol, Aida Habtezion
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI124566.
Abstract
Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPN). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPN suggests that vascular function is altered. Consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice, resulting from disturbed endothelial nitric oxide pathway and increased endothelial oxidative stress. This response was reproduced in wild-type mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for microvesicles effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes supressed their effect on oxidative stress. Antioxidants, such as simvastatin and N-acetyl-cysteine, improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPN are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears as promising therapeutic strategy in this setting.
Authors
Johanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurelie Plessier, Salma Merchant, Olivier Blanc-Brude, Michele Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N. Hatem, Chloe James, Jean-Luc Villeval, Chantal M. Boulanger, Pierre-Emmanuel Rautou
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134923.
Abstract
Background: Interventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naïve individuals. Method: Healthy, malaria-naïve adults were enrolled in two studies to assess the safety and infectivity and transmissibility of a new P. vivax isolate. Participants (Study 1; n=2, Study 2; n=24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes. Results: Parasitaemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Participants were infectious to Anopheles mosquitoes at peak gametocytemia 69% (11/16). Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture. Conclusion: We have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle. Trial registration: ACTRN12614000930684 and ACTRN12616000174482. Funding: (Australian) NHMRC Program Grant: 1132975 (Study 1). Bill & Melinda Gates Foundation (OPP1111147) (Study 2).
Authors
Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Gregory J. Robinson, Melanie Rampton, Suzanne Elliott, Anand Odedra, David S. Khoury, Emma Ballard, Todd B. Shelper, Leonardo Lucantoni, Vicky M. Avery, Stephan Chalon, Jörg J. Möhrle, James S. McCarthy
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133142.
Abstract
Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO>WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in BMDM cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI/improved OLT survival by suppressing p-p38 upregulation, ROS induction/HMGB1 translocation (CC1-KO>WT); while ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in sixty human donor liver biopsies correlated negatively with activation of ASK1/p-p38 axis; while low-CC1 levels associated with increased ROS/HMGB1 translocation, enhanced innate/adaptive immune responses and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of independent predictors for EAD in human OLT patients. Thus, as a checkpoint regulator of IR-stress/sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.
Authors
Kojiro Nakamura, Shoichi Kageyama, Fady M. Kaldas, Hirofumi Hirao, Takahiro Ito, Kentaro Kadono, Kenneth J. Dery, Hidenobu Kojima, David W. Gjertson, Rebecca A. Sosa, Maciej Kujawski, Ronald W. Busuttil, Elaine F. Reed, Jerzy W. Kupiec-Weglinski
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI128867.
Abstract
Hair cells are the mechanosensory receptors of the inner ear, responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely-used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular HSP70 (Heat Shock 70 kDa Protein). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, while inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair-cell specific expression of the known HSP70 receptor, Toll-like receptor 4 (TLR4), was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate non-autonomous hair cell survival. Exosomes may represent a novel class of nano-carriers for delivery of therapeutics against hearing loss.
Authors
Andrew M. Breglio, Lindsey A. May, Melanie Barzik, Nora C. Welsh, Shimon P. Francis, Tucker Q. Costain, Lizhen Wang, D. Eric Anderson, Ronald S. Petralia, Ya-Xian Wang, Thomas B. Friedman, Matthew J.A. Wood, Lisa L. Cunningham
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI132712.
Abstract
Background: The anti-programmed cell death 1 (PD-1) antibody pembrolizumab is clinically active against non-small cell lung cancer (NSCLC). In addition to T-cells, human natural killer (NK) cells, reported to have the potential to prolong the survival of advanced NSCLC patients, also express PD-1. This study aimed to investigate the safety and efficacy of pembrolizumab plus allogeneic NK cells in patients with previously treated advanced NSCLC. Methods: In total, 109 enrolled patients with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1% were randomly allocated to group A (55 patients, pembrolizumab plus NK cells) and group B (54 patients, pembrolizumab alone). The patients received intravenous pembrolizumab (10 mg/kg) once every 3 weeks and continued treatment until the occurrence of tumor progression or unacceptable toxicity. The patients in group A continuously received two cycles of NK cell therapy as one course of treatment. Results: In our study, Group A patients had better survival than group B patients (median overall survival [OS]: 15.5 months vs. 13.3 months; median progression-free survival [PFS]: 6.5 months vs. 4.3 months, P<0.05). In group A patients with a TPS ≥50%, the median OS and PFS were significantly prolonged. Moreover, the group A patients treated with multiple courses of NK cell infusion had better OS (18.5 months) than those who received a single course of NK cell infusion (13.5 months). Conclusions: Pembrolizumab plus NK cell therapy yielded improved survival benefits in patients with previously treated PD-L1-positive advanced NSCLC.
Authors
Mao Lin, Haihua Luo, Shuzhen Liang, Jibing Chen, Aihua Liu, Lizhi Niu, Yong Jiang
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI132374.
Abstract
Curing HIV infection will require the elimination of a reservoir of infected CD4+ T-cells that persists despite HIV-specific cytotoxic T-cell (CTL) responses. While viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. This resistance may have contributed to negative outcomes of clinical trials, where pharmacologic latency reversal has thus far failed to drive reductions in HIV reservoirs. Through transcriptional profiling, we herein identified over-expression of the pro-survival factor BCL-2 as a distinguishing feature of CD4+ T-cells that survived CTL killing. We show that the inducible HIV reservoir was disproportionately present in BCL-2hi subsets, in ex vivo CD4+ T-cells. Treatment with the BCL-2 antagonist ‘ABT-199’ alone was not sufficient to drive reductions in ex vivo viral reservoirs, when tested either alone or with a latency reversing agent (LRA). However, the triple combination of strong LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled the depletion of ex vivo viral reservoirs. Our results provide rationale for novel therapeutic approaches targeting HIV cure and, more generally, suggest consideration of BCL-2 antagonism as a means of enhancing CTL immunotherapy in other settings, such as cancer.
Authors
Yanqin Ren, Szu-Han Huang, Shabnum Patel, Winiffer D. Conce Alberto, Dean Magat, Dughan J. Ahimovic, Amanda B. Macedo, Ryan Durga, Dora Chan, Elizabeth Zale, Talia M. Mota, Ronald Truong, Thomas Rohwetter, Chase D. McCann, Colin M. Kovacs, Erika Benko, Avery Wimpelberg, Christopher M. Cannon, W. David Hardy, Alberto Bosque, Catherine M. Bollard, R. Brad Jones
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI134402.
Abstract
Whether mutations in cancer driver genes directly affect cancer immune phenotype and T cell immunity remains a standing question. ARID1A is a core member of the polymorphic BAF chromatin remodeling complex. ARID1A mutations occur in human cancers and drive cancer development. Here, we studied the molecular, cellular, and clinical impact of ARID1A aberrations on cancer immunity. We demonstrated that ARID1A aberrations resulted in limited chromatin accessibility to interferon (IFN) responsive genes, caused impaired IFN-gene expression, anemic T cell tumor infiltration, poor tumor immunity, and shortened host survival in many human cancer histologies as well as in murine cancer models. Impaired IFN signaling was associated with poor immunotherapy response. Mechanistically, ARID1A interacted with EZH2 via its carboxyl terminal and antagonized EZH2-mediated IFN responsiveness. Thus, the interaction between ARID1A and EZH2 defines cancer IFN-responsiveness and immune evasion. Our work indicates that cancer epigenetic driver mutations can shape cancer immune phenotype and immunotherapy.
Authors
Jing Li, Weichao Wang, Yajia Zhang, Marcin Cieślik, Jipeng Guo, Mengyao Tan, Michael D. Green, Weimin Wang, Heng Lin, Wei Li, Shuang Wei, Jiajia Zhou, Gaopeng Li, Xiaojun Jing, Linda Vatan, Lili Zhao, Benjamin Bitler, Rugang Zhang, Kathleen R. Cho, Yali Dou, Ilona Kryczek, Timothy A. Chan, David Huntsman, Arul M. Chinnaiyan, Weiping Zou
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI135099.
Abstract
Lymph node stromal cells (LNSC) regulate immunity through constructing lymphocyte niches. LNSC produced Laminin α5 (Lama5) regulates CD4 T cells but the underlying mechanisms of its functions are poorly understood. Here we showed depleting Lama5 in LNSC resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEV). Lama5 depletion affected LN structure with increased HEV, upregulated chemokines and cell adhesion molecules, and led to greater numbers of Treg in T cell zone. Mouse and human T cell transendothelial migration and T cell entry to LN were suppressed by Lama5 through the receptors a6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen specific CD4 T cell entry to the CR through HEV, suppressed T cell activation and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4:Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. The study delineated a stromal Lama5-T cell receptors axis that can be targeted for immune tolerance modulation.
Authors
Lushen Li, Marina W. Shirkey, Tianshu Zhang, Yanbao Xiong, Wenji Piao, Vikas Saxena, Christina Paluskievicz, Young S. Lee, Nicholas Toney, Benjamin M. Cerel, Qinshan Li, Thomas Simon, Kyle D. Smith, Keli L. Hippen, Bruce R. Blazar, Reza Abdi, Jonathan S. Bromberg
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130597.
Abstract
Plasmacytoid dendritic cells (pDCs) are robust producers of interferon α (IFNα) and one of the first immune cells to respond to simian immunodeficiency virus infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). An increased frequency of partially activated pDCs was observed in the blood prior to detection of HIV RNA. Concurrent with peak pDC frequency, there was a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased interferon regulatory factory 7 (IRF7) and NF-kB phosphorylation. Levels of phosphorylated IRF7 and NF-kB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data, from a limited cohort, provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.
Authors
Julie L. Mitchell, Hiroshi Takata, Roshell Muir, Donn J. Colby, Eugene Kroon, Trevor A. Crowell, Carlo Sacdalan, Suteeraporn Pinyakorn, Suwanna Pattamaswin, Khunthalee Benjapornpong, Rapee Trichavaroj, Randall L. Tressler, Lawrence Fox, Victoria R. Polonis, Diane L. Bolton, Frank Maldarelli, Sharon R. Lewin, Elias K. Haddad, Praphan Phanuphak, Merlin L. Robb, Nelson L. Michael, Mark de Souza, Nittaya Phanuphak, Jintanat Ananworanich, Lydie Trautmann
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133055.
Abstract
An in-depth understanding of immune escape mechanisms in cancer are likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several pre-clinical tumor models as well as clinical specimens, we report a newly identified mechanism whereby CD8+ T cell activation in response to PD-1 blockade induced a PD-L1-NLRP3 inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting anti-tumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic adaptive resistance mechanism to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.
Authors
Balamayooran Theivanthiran, Kathy S. Evans, Nicholas C. DeVito, Michael P. Plebanek, Michael Sturdivant, Lucas P. Wachsmuth, April K.S. Salama, Yubin Kang, David Hsu, Justin M. Balko, Douglas B. Johnson, Mark Starr, Andrew B. Nixon, Alisha Holtzhausen, Brent A. Hanks
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI130787.
Abstract
Background: Neurofibroma/schwannoma hybrid nerve sheath tumors (N/S HNSTs) are neoplasms associated with larger nerves that occur sporadically and in the context of schwannomatosis or neurofibromatosis type 2 or 1. Clinical management of N/S HNST is challenging, especially for large tumors, and established systemic treatments are lacking. Methods: We used next-generation sequencing and array-based DNA methylation profiling to determine the clinically actionable genomic and epigenomic landscapes of N/S HNST. Results: Whole-exome sequencing within a precision oncology program identified an activating mutation (p.Asp769Tyr) in the catalytic domain of the ERBB2 receptor tyrosine kinase in a patient with schwannomatosis-associated N/S HNST, and targeted treatment with the small-molecule ERBB inhibitor lapatinib led to prolonged clinical benefit and a lasting radiographic and metabolic response. Analysis of a multicenter validation cohort revealed recurrent ERBB2 mutations (p.Leu755Ser, p.Asp769Tyr, p.Val777Leu) in N/S HNSTs occurring in patients who met diagnostic criteria for sporadic schwannomatosis (3 of 7 patients), but not in N/S HNSTs arising in the context of neurofibromatosis (6 patients) or outside a tumor syndrome (1 patient), and showed that ERBB2-mutant N/S HNSTs cluster in a distinct subgroup of peripheral nerve sheath tumors based on genome-wide DNA methylation patterns. Conclusion: These findings uncover a key biological feature of N/S HNST that may have important diagnostic and therapeutic implications. Funding: This work was supported by grant H021 from DKFZ-HIPO. MWR and PNH have received fellowships from UCT Frankfurt, and MWR has received funding from the Frankfurt Research Funding Clinician Scientist Program.
Authors
Michael W. Ronellenfitsch, Patrick N. Harter, Martina Kirchner, Christoph Heining, Barbara Hutter, Laura Gieldon, Jens Schittenhelm, Martin U. Schuhmann, Marcos Tatagiba, Gerhard Marquardt, Marlies Wagner, Volker Endris, Christian H. Brandts, Victor-Felix Mautner, Evelin Schröck, Wilko Weichert, Benedikt Brors, Andreas von Deimling, Michel Mittelbronn, Joachim P. Steinbach, David E. Reuss, Hanno Glimm, Albrecht Stenzinger, Stefan Fröhling
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI131919.
Abstract
Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. Due to globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY-receptors represent a highly conserved, stress-activated system which is involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased NPY5-receptor (Y5R) expression in HCC which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peri-tumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R-activation. Transforming growth factor beta 1 (TGFβ1) was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY-conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R-activation and function in liver cancer. The TGFβ-NPY-Y5R-axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.
Authors
Peter Dietrich, Laura Wormser, Valerie Fritz, Tatjana Seitz, Monica De Maria, Alexandra Schambony, Andreas E. Kremer, Claudia Günther, Timo Itzel, Wolfgang E. Thasler, Andreas Teufel, Jonel Trebicka, Arndt Hartmann, Markus F. Neurath, Stephan von Hörsten, Anja Bosserhoff, Claus Hellerbrand
Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)