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Review

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Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy
Xia Liu, … , Daniel F. Hoft, Guangyong Peng
Xia Liu, … , Daniel F. Hoft, Guangyong Peng
Published March 2, 2020
Citation Information: J Clin Invest. 2020;130(3):1073-1083. https://doi.org/10.1172/JCI133679.
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Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy

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Abstract

The functional state of the preexisting T cells in the tumor microenvironment is a key determinant for effective antitumor immunity and immunotherapy. Increasing evidence suggests that immunosenescence is an important state of T cell dysfunction that is distinct from exhaustion, a key strategy used by malignant tumors to evade immune surveillance and sustain the suppressive tumor microenvironment. Here, we discuss the phenotypic and functional characteristics of senescent T cells and their role in human cancers. We also explore the possible mechanisms and signaling pathways responsible for induction of T cell senescence by malignant tumors, and then discuss potential strategies to prevent and/or reverse senescence in tumor-specific T cells. A better understanding of these critical issues should provide novel strategies to enhance cancer immunotherapy.

Authors

Xia Liu, Daniel F. Hoft, Guangyong Peng

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The multifaceted role of ischemia/reperfusion in sickle cell anemia
Robert P. Hebbel, … , John D. Belcher, Gregory M. Vercellotti
Robert P. Hebbel, … , John D. Belcher, Gregory M. Vercellotti
Published March 2, 2020
Citation Information: J Clin Invest. 2020;130(3):1062-1072. https://doi.org/10.1172/JCI133639.
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The multifaceted role of ischemia/reperfusion in sickle cell anemia

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Abstract

Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury (e.g., acute chest syndrome) or the systematization of inflammation (e.g., multifocal arteriopathy). Indeed, by fashioning an underlying template of endothelial dysfunction and vulnerability, the robust inflammatory systematization no doubt contributes to all sickle pathology. In this Review, we highlight I/R–targeting therapeutics shown to improve microvascular blood flow in sickle transgenic mice undergoing I/R, and we suggest how such insights might be translated into human therapeutic strategies.

Authors

Robert P. Hebbel, John D. Belcher, Gregory M. Vercellotti

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Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes
Amit Verma, … , Rami Komrokji, Ravi Kumar
Amit Verma, … , Rami Komrokji, Ravi Kumar
Published January 21, 2020
Citation Information: J Clin Invest. 2020. https://doi.org/10.1172/JCI133678.
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Biological basis for efficacy of activin receptor ligand traps in myelodysplastic syndromes

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Abstract

Signaling by the TGF-β superfamily is important in the regulation of hematopoiesis and is dysregulated in myelodysplastic syndromes (MDSs), contributing to ineffective hematopoiesis and clinical cytopenias. TGF-β, activins, and growth differentiation factors exert inhibitory effects on red cell formation by activating canonical SMAD2/3 pathway signaling. In this Review, we summarize evidence that overactivation of SMAD2/3 signaling pathways in MDSs causes anemia due to impaired erythroid maturation. We also describe the basis for biological activity of activin receptor ligand traps, novel fusion proteins such as luspatercept that are promising as erythroid maturation agents to alleviate anemia and related comorbidities in MDSs and other conditions characterized by impaired erythroid maturation.

Authors

Amit Verma, Rajasekhar N.V.S. Suragani, Srinivas Aluri, Nishi Shah, Tushar D. Bhagat, Mark J. Alexander, Rami Komrokji, Ravi Kumar

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Time to dissect the autoimmune etiology of cancer antibody immunotherapy
Michael Dougan, Massimo Pietropaolo
Michael Dougan, Massimo Pietropaolo
Published January 2, 2020
Citation Information: J Clin Invest. 2020;130(1):51-61. https://doi.org/10.1172/JCI131194.
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Time to dissect the autoimmune etiology of cancer antibody immunotherapy

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Abstract

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory “checkpoint” receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

Authors

Michael Dougan, Massimo Pietropaolo

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It’s about time: clocks in the developing lung
Colleen M. Bartman, … , Aleksey Matveyenko, Y.S. Prakash
Colleen M. Bartman, … , Aleksey Matveyenko, Y.S. Prakash
Published January 2, 2020
Citation Information: J Clin Invest. 2020;130(1):39-50. https://doi.org/10.1172/JCI130143.
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It’s about time: clocks in the developing lung

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Abstract

The discovery of peripheral intracellular clocks revealed circadian oscillations of clock genes and their targets in all cell types, including those in the lung, sparking exploration of clocks in lung disease pathophysiology. While the focus has been on the role of these clocks in adult airway diseases, clock biology is also likely to be important in perinatal lung development, where it has received far less attention. Historically, fetal circadian rhythms have been considered irrelevant owing to lack of external light exposure, but more recent insights into peripheral clock biology raise questions of clock emergence, its concordance with tissue-specific structure/function, the interdependence of clock synchrony and functionality in perinatal lung development, and the possibility of lung clocks in priming the fetus for postnatal life. Understanding the perinatal molecular clock may unravel mechanistic targets for chronic airway disease across the lifespan. With current research providing more questions than answers, it is about time to investigate clocks in the developing lung.

Authors

Colleen M. Bartman, Aleksey Matveyenko, Y.S. Prakash

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Targeting innate immunity for tuberculosis vaccination
Shabaana A. Khader, … , Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
Shabaana A. Khader, … , Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3482-3491. https://doi.org/10.1172/JCI128877.
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Targeting innate immunity for tuberculosis vaccination

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Abstract

Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a rapid and robust immune response upon encounter with Mycobacterium tuberculosis, thus achieving long-lasting protection against infection. Recent studies have shown, however, that innate immune cell populations such as myeloid cells and NK cells also undergo functional adaptation after infection or vaccination, a de facto innate immune memory that is also termed trained immunity. Experimental and epidemiological data have shown that induction of trained immunity contributes to the beneficial heterologous effects of vaccines such as bacille Calmette-Guérin (BCG), the licensed TB vaccine. Moreover, increasing evidence argues that trained immunity also contributes to the anti-TB effects of BCG vaccination. An interaction among immunological signals, metabolic rewiring, and epigenetic reprogramming underlies the molecular mechanisms mediating trained immunity in myeloid cells and their bone marrow progenitors. Future studies are warranted to explore the untapped potential of trained immunity to develop a future generation of TB vaccines that would combine innate and adaptive immune memory induction.

Authors

Shabaana A. Khader, Maziar Divangahi, Willem Hanekom, Philip C. Hill, Markus Maeurer, Karen W. Makar, Katrin D. Mayer-Barber, Musa M. Mhlanga, Elisa Nemes, Larry S. Schlesinger, Reinout van Crevel, Ramakrishna Vankalayapati, Ramnik J. Xavier, Mihai G. Netea, on behalf of the Bill and Melinda Gates Foundation Collaboration for TB Vaccine Discovery Innate Immunity Working Group18

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Functional diversification of IgGs through Fc glycosylation
Taia T. Wang, Jeffrey V. Ravetch
Taia T. Wang, Jeffrey V. Ravetch
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3492-3498. https://doi.org/10.1172/JCI130029.
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Functional diversification of IgGs through Fc glycosylation

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Abstract

IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through Fcγ receptors (FcγRs), which transduce interactions with immune complexes, leading to a variety of cellular outcomes depending on the FcγRs and cell types engaged. Which FcγRs and cell types will be engaged during an immune response depends on the structure of Fc domains within immune complexes that are formed when IgGs bind to cognate antigen(s). Recent studies have revealed an unexpected degree of structural variability in IgG Fc domains among people, driven primarily by differences in IgG subclasses and N-linked glycosylation of the CH2 domain. This translates, in turn, to functional immune diversification through type I and type II FcγR–mediated cellular functions. For example, Fc domain sialylation triggers conformational changes of IgG1 that enable interactions with type II FcγRs; these receptors mediate cellular functions including antiinflammatory activity or definition of thresholds for B cell selection based on B cell receptor affinity. Similarly, presence or absence of a core fucose alters type I FcγR binding of IgG1 by modulating the Fc’s affinity for FcγRIIIa, thereby altering its proinflammatory activity. How heterogeneity in IgG Fc domains contributes to human immune diversity is now being elucidated, including impacts on vaccine responses and susceptibility to disease and its sequelae during infections. Here, we discuss how Fc structures arising from sialylation and fucosylation impact immunity, focusing on responses to vaccination and infection. We also review work defining individual differences in Fc glycosylation, regulation of Fc glycosylation, and clinical implications of these pathways.

Authors

Taia T. Wang, Jeffrey V. Ravetch

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Killers 2.0: NK cell therapies at the forefront of cancer control
Jonathan J. Hodgins, … , Rebecca C. Auer, Michele Ardolino
Jonathan J. Hodgins, … , Rebecca C. Auer, Michele Ardolino
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3499-3510. https://doi.org/10.1172/JCI129338.
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Killers 2.0: NK cell therapies at the forefront of cancer control

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Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells’ critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor–expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance.

Authors

Jonathan J. Hodgins, Sarwat T. Khan, Maria M. Park, Rebecca C. Auer, Michele Ardolino

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The supply chain of human pancreatic β cell lines
Raphael Scharfmann, … , Willem Staels, Olivier Albagli
Raphael Scharfmann, … , Willem Staels, Olivier Albagli
Published September 3, 2019
Citation Information: J Clin Invest. 2019;129(9):3511-3520. https://doi.org/10.1172/JCI129484.
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The supply chain of human pancreatic β cell lines

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Abstract

Patients with type 1 or type 2 diabetes have an insufficiency in their functional β cell mass. To advance diabetes treatment and to work toward a cure, a better understanding of how to protect the pancreatic β cells against autoimmune or metabolic assaults (e.g., obesity, gestation) will be required. Over the past decades, β cell protection has been extensively investigated in rodents both in vivo and in vitro using isolated islets or rodent β cell lines. Transferring these rodent data to humans has long been challenging, at least partly for technical reasons: primary human islet preparations were scarce and functional human β cell lines were lacking. In 2011, we described a robust protocol of targeted oncogenesis in human fetal pancreas and produced the first functional human β cell line, and in subsequent years additional lines with specific traits. These cell lines are currently used by more than 150 academic and industrial laboratories worldwide. In this Review, we first explain how we developed the human β cell lines and why we think we succeeded where others, despite major efforts, did not. Next, we discuss the use of such functional human β cell lines and share some perspectives on their use to advance diabetes research.

Authors

Raphael Scharfmann, Willem Staels, Olivier Albagli

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The gut-bone axis: how bacterial metabolites bridge the distance
Mario M. Zaiss, … , Georg Schett, Roberto Pacifici
Mario M. Zaiss, … , Georg Schett, Roberto Pacifici
Published July 15, 2019
Citation Information: J Clin Invest. 2019. https://doi.org/10.1172/JCI128521.
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The gut-bone axis: how bacterial metabolites bridge the distance

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Abstract

The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

Authors

Mario M. Zaiss, Rheinallt M. Jones, Georg Schett, Roberto Pacifici

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