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.
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
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.
Sonia Guedan, Aviv Madar, Victoria Casado-Medrano, Carolyn E. Shaw, Anna Wing, Fang Liu, Regina M. Young, Carl H. June, Avery D. Posey Jr.
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.
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
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.
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
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).
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
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.
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
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.
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
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.
Mao Lin, Haihua Luo, Shuzhen Liang, Jibing Chen, Aihua Liu, Lizhi Niu, Yong Jiang
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.
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
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.
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
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