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Issue published March 15, 2022 Previous issue

On the cover: Sexually dimorphic response in muscle to intermittent glucocorticoid treatment

Salamone et al. report that once-weekly glucocorticoid exposure enhances muscle performance in both male and female mice through distinct mechanisms. Myosin heavy chain isoforms distinguish oxidative (Myh2, blue) and glycolytic (Myh4, red) myofibers in tibialis anterior muscle of male mice treated intermittently with glucocorticoids.

Review Series
Abstract

Obesity has reached epidemic proportions and is a major contributor to insulin resistance (IR) and type 2 diabetes (T2D). Importantly, IR and T2D substantially increase the risk of cardiovascular (CV) disease. Although there are successful approaches to maintain glycemic control, there continue to be increased CV morbidity and mortality associated with metabolic disease. Therefore, there is an urgent need to understand the cellular and molecular processes that underlie cardiometabolic changes that occur during obesity so that optimal medical therapies can be designed to attenuate or prevent the sequelae of this disease. The vascular endothelium is in constant contact with the circulating milieu; thus, it is not surprising that obesity-driven elevations in lipids, glucose, and proinflammatory mediators induce endothelial dysfunction, vascular inflammation, and vascular remodeling in all segments of the vasculature. As cardiometabolic disease progresses, so do pathological changes in the entire vascular network, which can feed forward to exacerbate disease progression. Recent cellular and molecular data have implicated the vasculature as an initiating and instigating factor in the development of several cardiometabolic diseases. This Review discusses these findings in the context of atherosclerosis, IR and T2D, and heart failure with preserved ejection fraction. In addition, novel strategies to therapeutically target the vasculature to lessen cardiometabolic disease burden are introduced.

Authors

Nabil E. Boutagy, Abhishek K. Singh, William C. Sessa

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Reviews
Abstract

Natural killer (NK) cells are innate immune cells that are critical to the body’s antitumor and antimetastatic defense. As such, novel therapies are being developed to utilize NK cells as part of a next generation of immunotherapies to treat patients with metastatic disease. Therefore, it is essential for us to examine how metastatic cancer cells and NK cells interact with each other throughout the metastatic cascade. In this Review, we highlight the recent body of work that has begun to answer these questions. We explore how the unique biology of cancer cells at each stage of metastasis alters fundamental NK cell biology, including how cancer cells can evade immunosurveillance and co-opt NK cells into cells that promote metastasis. We also discuss the translational potential of this knowledge.

Authors

Isaac S. Chan, Andrew J. Ewald

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Abstract

The COVID-19 pandemic has elevated mRNA vaccines to global recognition due to their unprecedented success rate in protecting against a deadly virus. This international success is underscored by the remarkable versatility, favorable immunogenicity, and overall safety of the mRNA platform in diverse populations. Although mRNA vaccines have been studied in preclinical models and patients with cancer for almost three decades, development has been slow. The recent technological advances responsible for the COVID-19 vaccines have potential implications for successfully adapting this vaccine platform for cancer therapeutics. Here we discuss the lessons learned along with the chemical, biologic, and immunologic adaptations needed to optimize mRNA technology to successfully treat cancers.

Authors

Amanda L. Huff, Elizabeth M. Jaffee, Neeha Zaidi

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Commentaries
Abstract

Cardiomyocyte hypertrophy is an integral part of cardiac remodeling that occurs under physiological or pathological stresses. It can lead to heart failure in a pathological form or oppose functional deterioration in a compensatory one. The mechanisms underlying an adaptive outcome of hypertrophy are ill defined. In this issue of the JCI, Kashihara et al. explored the role of the Yes-associated protein 1 (YAP) transcription factor in the heart, using cell culturing and mouse models. YAP activity was found to be associated with changes in genes of the glycolytic and auxiliary pathways under stress. Notably, YAP upregulated glucose transporter 1 (GLUT1), and inhibition of GLUT1 blocked YAP-induced hypertrophy but worsened heart function. These findings suggest that YAP is a regulator of metabolic reprogramming in the heart during compensatory hypertrophy. This insight may help in the development of future therapies for heart failure.

Authors

Chen Gao, Yibin Wang

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Abstract

Tumor-infiltrating B cells exert antitumor effects by producing antibodies against tumor-associated antigens. Conversely, B cells may promote tumors through the production of factors that dampen antitumor immunity. In this issue of the JCI, Bing Yang, Zhen Zhang, et al. investigated the roles of B cell receptor (BCR) signaling in antitumor immunity, focusing on the role of an Asia-specific variant of human immunoglobulin G1 (IgG1) containing a Gly396 to Arg396 substitution (hIgG1-G396R) in colorectal cancer (CRC). Epidemiological analysis revealed an association between hIgG1-G396R and progression-free survival in CRC. Human samples and mouse models of CRC showed plasma cells, as opposed to B cells, infiltrating the tumor microenvironment. Notably, patients with the hIgG1-G396R variant had increased CD8+ T cells, dendritic cells, and tertiary lymphoid structure density. These findings indicate that the hIgG1-G396R variant represses tumorigenesis by enhancing B cell responses, and suggest that modulating BCR signaling could improve the efficacy of immunotherapy in cancer.

Authors

Jian Ye, Peter P. Lee

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Abstract

Lyme disease is the most common tick-borne disease in North America and Europe, however, current biomarkers inconsistently detect the disease. In this issue of the JCI, Gwynne et al. revealed how the Lyme disease agent Borrelia burgdorferi relies on host lipids for growth. The authors used a murine model to show that B. burgdorferi infection led to the production of antibodies against phospholipids, possibly as a consequence of incorporation into the spirochete membrane. Antibodies were induced against phosphatidic acid, phosphatidylcholine, and phosphatidylserine. Notably, no antibodies against cardiolipin were found, distinguishing Lyme disease from syphilis and some other diseases. Sera samples from patients with Lyme disease suggested that these antibodies may help diagnose B. burgdorferi infection and that antibody titers may effectively indicate the response to treatment. These findings suggest that B. burgdorferi–induced anti-lipid antibodies, in conjunction with a careful clinical assessment, may aid in the diagnosis of Lyme disease.

Authors

Gunjan Arora, Thomas Hart, Erol Fikrig

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Abstract

Cardiovascular diseases are a leading cause of mortality and disability worldwide. Hypertension, a major risk factor for these diseases, remains difficult to treat despite numerous drugs being available. In this issue of the JCI, Failer et al. show that the endogenous antiinflammatory agent developmental endothelial locus-1 (DEL-1) decreased blood pressure and cardiac and aortic hypertrophy in mouse models of hypertension through reduction in αvβ3 integrin–dependent metalloproteinase activity and immune cell recruitment, leading to reduced production of proinflammatory cytokines in cardiovascular tissues. This study offers an alternative in the treatment of hypertension-mediated organ damage through the immunomodulatory effect of DEL-1.

Authors

Daniel Henrion

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Research Articles
Abstract

The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous antiinflammatory factor, in angiotensin II– (ANGII–) and deoxycorticosterone acetate–salt–induced (DOCA-salt–induced) cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1 mice) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening, and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy and interstitial and perivascular coronary fibrosis and improved left ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3 integrin–dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3 integrin–dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased recruitment of inflammatory cells and reduced production of proinflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.

Authors

Theresa Failer, Michael Amponsah-Offeh, Aleš Neuwirth, Ioannis Kourtzelis, Pallavi Subramanian, Peter Mirtschink, Mirko Peitzsch, Klaus Matschke, Sems M. Tugtekin, Tetsuhiro Kajikawa, Xiaofei Li, Anne Steglich, Florian Gembardt, Annika C. Wegner, Christian Hugo, George Hajishengallis, Triantafyllos Chavakis, Andreas Deussen, Vladimir Todorov, Irakli Kopaliani

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Abstract

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I–like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.

Authors

Younglang Lee, Alex W. Wessel, Jiazhi Xu, Julia G. Reinke, Eries Lee, Somin M. Kim, Amy P. Hsu, Jevgenia Zilberman-Rudenko, Sha Cao, Clinton Enos, Stephen R. Brooks, Zuoming Deng, Bin Lin, Adriana A. de Jesus, Daniel N. Hupalo, Daniela G.P. Piotto, Maria T. Terreri, Victoria R. Dimitriades, Clifton L. Dalgard, Steven M. Holland, Raphaela Goldbach-Mansky, Richard M. Siegel, Eric P. Hanson

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Abstract

New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1–positive GBM to ionizing radiation by elevated production of nitric oxide (˙NO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.

Authors

Nabil Hajji, Juan Garcia-Revilla, Manuel Sarmiento Soto, Richard Perryman, Jake Symington, Chad C. Quarles, Deborah R. Healey, Yijie Guo, Manuel Luis Orta-Vázquez, Santiago Mateos-Cordero, Khalid Shah, John Bomalaski, Giulio Anichini, Andreas G. Tzakos, Timothy Crook, Kevin O’Neill, Adrienne C. Scheck, Jose Luis Venero, Nelofer Syed

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Abstract

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, containing GBM stem cells (GSCs) that contribute to therapeutic resistance and relapse. Exposing potential GSC vulnerabilities may provide therapeutic strategies against GBM. Here, we interrogated the role of adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA 1 (ADAR1) in GSCs and found that both ADAR1 and global RNA editomes were elevated in GSCs compared with normal neural stem cells. ADAR1 inactivation or blocking of the upstream JAK/STAT pathway through TYK2 inhibition impaired GSC self-renewal and stemness. Downstream of ADAR1, RNA editing of the 3′-UTR of GM2A, a key ganglioside catabolism activator, proved to be critical, as interference with ganglioside catabolism and disruption of ADAR1 showed a similar functional impact on GSCs. These findings reveal that RNA editing links ganglioside catabolism to GSC self-renewal and stemness, exposing a potential vulnerability of GBM for therapeutic intervention.

Authors

Li Jiang, Yajing Hao, Changwei Shao, Qiulian Wu, Briana C. Prager, Ryan C. Gimple, Gabriele Sulli, Leo J.Y. Kim, Guoxin Zhang, Zhixin Qiu, Zhe Zhu, Xiang-Dong Fu, Jeremy N. Rich

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Abstract

Genetic variants at the SORT1 locus in humans, which cause increased SORT1 expression in the liver, are significantly associated with reduced plasma levels of LDL cholesterol and apolipoprotein B (apoB). However, the role of hepatic sortilin remains controversial, as genetic deletion of sortilin in mice has resulted in variable and conflicting effects on apoB secretion. Here, we found that Sort1-KO mice on a chow diet and several Sort1-deficient hepatocyte lines displayed no difference in apoB secretion. When these models were challenged with high-fat diet or ER stress, the loss of Sort1 expression resulted in a significant increase in apoB-100 secretion. Sort1-overexpression studies yielded reciprocal results. Importantly, carriers of SORT1 variant with diabetes had larger decreases in plasma apoB, TG, and VLDL and LDL particle number as compared with people without diabetes with the same variants. We conclude that, under basal nonstressed conditions, loss of sortilin has little effect on hepatocyte apoB secretion, whereas, in the setting of lipid loading or ER stress, sortilin deficiency leads to increased apoB secretion. These results are consistent with the directionality of effect in human genetics studies and suggest that, under stress conditions, hepatic sortilin directs apoB toward lysosomal degradation rather than secretion, potentially serving as a quality control step in the apoB secretion pathway in hepatocytes.

Authors

Donna M. Conlon, Carolin V. Schneider, Yi-An Ko, Amrith Rodrigues, Kathy Guo, Nicholas J. Hand, Daniel J. Rader

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Abstract

Immune checkpoint blockade (ICB) therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses because of the emergence of immune-refractory tumors that disrupt the amplification of antitumor immunity. Therefore, the identification of clinically available targets that restrict antitumor immunity is required to develop potential combination therapies. Here, using transcriptomic data on patients with cancer treated with programmed cell death protein 1 (PD-1) therapy and newly established mouse preclinical anti–PD-1 therapy–refractory models, we identified NANOG as a factor restricting the amplification of the antitumor immunity cycle, thereby contributing to the immune-refractory feature of the tumor microenvironment (TME). Mechanistically, NANOG induced insufficient T cell infiltration and resistance to CTL-mediated killing via the histone deacetylase 1–dependent (HDAC1-dependent) regulation of CXCL10 and MCL1, respectively. Importantly, HDAC1 inhibition using an actionable agent sensitized NANOGhi immune-refractory tumors to PD-1 blockade by reinvigorating the antitumor immunity cycle. Thus, our findings implicate the NANOG/HDAC1 axis as a central molecular target for controlling immune-refractory tumors and provide a rationale for combining HDAC inhibitors to reverse the refractoriness of tumors to ICB therapy.

Authors

Se Jin Oh, Hyo-Jung Lee, Kwon-Ho Song, Suyeon Kim, Eunho Cho, Jaeyoon Lee, Marcus W. Bosenberg, Tae Woo Kim

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Abstract

Glucocorticoid steroids are commonly prescribed for many inflammatory conditions, but chronic daily use produces adverse effects, including muscle wasting and weakness. In contrast, shorter glucocorticoid pulses may improve athletic performance, although the mechanisms remain unclear. Muscle is sexually dimorphic and comparatively little is known about how male and female muscles respond to glucocorticoids. We investigated the impact of once-weekly glucocorticoid exposure on skeletal muscle performance comparing male and female mice. One month of once-weekly glucocorticoid dosing improved muscle specific force in both males and females. Transcriptomic profiling of isolated myofibers identified a striking sexually dimorphic response to weekly glucocorticoids. Male myofibers had increased expression of genes in the IGF1/PI3K pathway and calcium handling, while female myofibers had profound upregulation of lipid metabolism genes. Muscles from weekly prednisone–treated males had improved calcium handling, while comparably treated female muscles had reduced intramuscular triglycerides. Consistent with altered lipid metabolism, weekly prednisone–treated female mice had greater endurance relative to controls. Using chromatin immunoprecipitation, we defined a sexually dimorphic chromatin landscape after weekly prednisone. These results demonstrate that weekly glucocorticoid exposure elicits distinct pathways in males versus females, resulting in enhanced performance.

Authors

Isabella M. Salamone, Mattia Quattrocelli, David Y. Barefield, Patrick G. Page, Ibrahim Tahtah, Michele Hadhazy, Garima Tomar, Elizabeth M. McNally

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Abstract

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart against acute blood pressure elevation. The nuclear effector of the Hippo pathway, Yes-associated protein 1 (YAP), is activated and mediates compensatory cardiac hypertrophy in response to acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn caused accumulation of intermediates and metabolites of the glycolytic, auxiliary, and anaplerotic pathways during acute PO. Cardiac hypertrophy was inhibited and heart failure was exacerbated in mice with YAP haploinsufficiency in the presence of acute PO. However, normalization of GLUT1 rescued the detrimental phenotype. PO induced the accumulation of glycolytic metabolites, including l-serine, l-aspartate, and malate, in a YAP-dependent manner, thereby promoting cardiac hypertrophy. YAP upregulated the GLUT1 gene through interaction with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy through activation of the Warburg effect.

Authors

Toshihide Kashihara, Risa Mukai, Shin-ichi Oka, Peiyong Zhai, Yasuki Nakada, Zhi Yang, Wataru Mizushima, Tsutomu Nakahara, Junco S. Warren, Maha Abdellatif, Junichi Sadoshima

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Abstract

A close association with its vertebrate and tick hosts allows Borrelia burgdorferi, the bacterium responsible for Lyme disease, to eliminate many metabolic pathways and instead scavenge key nutrients from the host. A lipid-defined culture medium was developed to demonstrate that exogenous lipids are an essential nutrient of B. burgdorferi, which can accumulate intact phospholipids from its environment to support growth. Antibody responses to host phospholipids were studied in mice and humans using an antiphospholipid ELISA. Several of these environmentally acquired phospholipids including phosphatidylserine and phosphatidic acid, as well as borrelial phosphatidylcholine, are the targets of antibodies that arose early in infection in the mouse model. Patients with acute infections demonstrated antibody responses to the same lipids. The elevation of antiphospholipid antibodies predicted early infection with better sensitivity than did the standardized 2-tier tests currently used in diagnosis. Sera obtained from patients with Lyme disease before and after antibiotic therapy showed declining antiphospholipid titers after treatment. Further study will be required to determine whether these antibodies have utility in early diagnosis of Lyme disease, tracking of the response to therapy, and diagnosis of reinfection, areas in which current standardized tests are inadequate.

Authors

Peter J. Gwynne, Luke H. Clendenen, Siu-Ping Turk, Adriana R. Marques, Linden T. Hu

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Abstract

BMP6 is a central cytokine in the induction of Sjögren’s syndrome–associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity.

Authors

Ying-Qian Mo, Hiroyuki Nakamura, Tsutomu Tanaka, Toshio Odani, Paola Perez, Youngmi Ji, Benjamin N. French, Thomas J.F. Pranzatelli, Drew G. Michael, Hongen Yin, Susan S. Chow, Maryam Khalaj, Sandra A. Afione, Changyu Zheng, Fabiola Reis Oliveira, Ana Carolina F. Motta, Alfredo Ribeiro-Silva, Eduardo M. Rocha, Cuong Q. Nguyen, Masayuki Noguchi, Tatsuya Atsumi, Blake M. Warner, John A. Chiorini

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Abstract

Background Bacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODS To evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTS Topical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, and soluble immune markers of epithelial barrier disruption. Although the vaginal microbiota shifted to dominance by L. iners or L. jensenii, this proportional shift was primarily driven by a 2 to 4 log10–fold reduction in BV-associated bacteria absolute abundance. BV treatment induced no change in the absolute abundance of L. crispatus or L. iners and only minor (<1 log10–fold) increases in L. gasseri and L. jensenii that were not independently associated with reduced inflammation in multivariable models.CONCLUSION The genital immune benefits that are associated with Lactobacillus dominance after BV treatment were not directly attributable to an absolute increase in lactobacilli, but rather to the loss of BV-associated bacteria.Trial REGISTRATION Participants were recruited as part of a randomized controlled trial (ClinicalTrials.gov NCT02766023) from 2016 to 2019.FUNDING Canadian Institutes of Health Research (PJT-156123) and the National Institute of Allergy and Infectious Diseases (HHSN2722013000141 and HHSN27200007).

Authors

Eric Armstrong, Anke Hemmerling, Steve Miller, Kerianne E. Burke, Sara J. Newmann, Sheldon R. Morris, Hilary Reno, Sanja Huibner, Maria Kulikova, Rachel Liu, Emily D. Crawford, Gloria R. Castañeda, Nico Nagelkerke, Bryan Coburn, Craig R. Cohen, Rupert Kaul

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Abstract

Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1+ plasma cells, CD8+ T cells, CD103+ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen–specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8+ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1+ memory B cells in tumors could improve immunotherapy outcomes.

Authors

Bing Yang, Zhen Zhang, Xiangjun Chen, Xu-Yan Wang, Shishang Qin, Liaoqi Du, Changjiang Yang, Liyu Zhu, Wenbo Sun, Yongjie Zhu, Qinwen Zheng, Shidong Zhao, Quan Wang, Long Zhao, Yilin Lin, Jinghe Huang, Fan Wu, Lu Lu, Fei Wang, Wenjie Zheng, Xiao-Hua Zhou, Xiaozhen Zhao, Ziye Wang, Sun Xiao-Lin, Yingjiang Ye, Shan Wang, Zhanguo Li, Hai Qi, Zemin Zhang, Dong-Ming Kuang, Lei Zhang, Zhanlong Shen, Wanli Liu

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Abstract

Blood vessel abnormalization alters cancer cell metabolism and promotes cancer dissemination and metastasis. However, the biological features of the abnormalized blood vessels that facilitate cancer progression and whether they can be targeted therapeutically have not been fully investigated. Here, we found that an axon guidance molecule, fibronectin leucine-rich transmembrane protein 2 (FLRT2), is expressed preferentially in abnormalized vessels of advanced colorectal cancers in humans and that its expression correlates negatively with long-term survival. Endothelial cell–specific deletion of Flrt2 in mice selectively pruned abnormalized vessels, resulting in a unique metabolic state termed “oxygen-glucose uncoupling,” which suppressed tumor metastasis. Moreover, Flrt2 deletion caused an increase in the number of mature vessels, resulting in a significant increase in the antitumor effects of immune checkpoint blockers. Mechanistically, we found that FLRT2 forms noncanonical interendothelial adhesions that safeguard against oxidative stress through homophilic binding. Together, our results demonstrated the existence of tumor-specific interendothelial adhesions that enable abnormalized vessels to facilitate cancer aggressiveness. Targeting this type of adhesion complex could be a safe and effective therapeutic option to suppress cancer progression.

Authors

Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota

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Abstract

De novo and acquired resistance are major impediments to the efficacy of conventional and targeted cancer therapy. In unselected gastric cancer (GC) patients with advanced disease, trials combining chemotherapy and an anti-EGFR monoclonal antibody have been largely unsuccessful. In an effort to identify biomarkers of resistance so as to better select patients for such trials, we screened the secretome of chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of glycoprotein hormones, were markedly increased in the conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on chemotherapy. CGA levels in plasma increased in GC patients who received chemotherapy, and this increase was correlated with reduced responsiveness to chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to chemotherapy. Based on this circuit, combination strategies involving anti-EGFR therapies or targeting CGA with microRNAs (miR-708-3p and miR-761) restored chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive biomarker and therapeutic target in chemoresistant GC.

Authors

Tianyu Cao, Yuanyuan Lu, Qi Wang, Hongqiang Qin, Hongwei Li, Hao Guo, Minghui Ge, Sarah E. Glass, Bhuminder Singh, Wenyao Zhang, Jiaqiang Dong, Feng Du, Airong Qian, Ye Tian, Xin Wang, Cunxi Li, Kaichun Wu, Daiming Fan, Yongzhan Nie, Robert J. Coffey, Xiaodi Zhao

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Abstract

Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

Authors

Camilo A. Ruiz-Bedoya, Filipa Mota, Elizabeth W. Tucker, Farina J. Mahmud, Maria I. Reyes-Mantilla, Clara Erice, Melissa Bahr, Kelly Flavahan, Patricia de Jesus, John Kim, Catherine A. Foss, Charles A. Peloquin, Dima A. Hammoud, Alvaro A. Ordonez, Carlos A. Pardo, Sanjay K. Jain

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Abstract

BACKGROUND Immunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last.METHODS We performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTS We found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2–infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSION Short-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDING This study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018–2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).

Authors

Alessio Mazzoni, Anna Vanni, Michele Spinicci, Giulia Lamacchia, Seble Tekle Kiros, Arianna Rocca, Manuela Capone, Nicoletta Di Lauria, Lorenzo Salvati, Alberto Carnasciali, Elisabetta Mantengoli, Parham Farahvachi, Lorenzo Zammarchi, Filippo Lagi, Maria Grazia Colao, Francesco Liotta, Lorenzo Cosmi, Laura Maggi, Alessandro Bartoloni, Gian Maria Rossolini, Francesco Annunziato

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Retraction
Abstract

Authors

Xian-Yang Li, Indrajit Das, Ailin Lepletier, Venkateswar Addala, Tobias Bald, Kimberley Stannard, Deborah Barkauskas, Jing Liu, Amelia Roman Aguilera, Kazuyoshi Takeda, Matthias Braun, Kyohei Nakamura, Sebastien Jacquelin, Steven W. Lane, Michele W.L. Teng, William C. Dougall, Mark J. Smyth

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Abstract

As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. While it was demonstrated that anti-platelet drugs suppress growth of abdominal aortic aneurysms (AAA) in patients, we revealed a certain degree of platelet reactivity persisted in spite of aspirin therapy urging us to consider additional anti-platelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors (ORs), and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13 which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies reveal that ORs regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.

Authors

Craig N. Morrell, Doran Mix, Anu Aggarwal, Rohan Bhandari, Matthew Godwin, A. Phillip Owens III, Sean P. Lyden, Adam Doyle, Krystin Krauel, Matthew T. Rondina, Amy Mohan, Charles J. Lowenstein, Sharon Shim, Shaun Stauffer, Vara Prasad Josyula, Sara K. Ture, David I. Yule, Larry E. Wagner III, John M. Ashton, Ayman Elbadawi, Scott J. Cameron

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Abstract

BACKGROUND. Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardio-respiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown. METHODS. Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12-weeks of cycling can recuperate clinical, and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients. RESULTS. DM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Lastly, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity. CONCLUSION. With no available cures, our data supports the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology. TRIAL REGISTRATION. This trial was approved by the HiREB committee (#7901) and registered under ClinicalTrials.gov (NCT04187482). FUNDING. This work was primarily supported by Neil and Leanne Petroff. This study was also supported by a Canadian Institutes of Health Research Foundation Grant to MAT (#143325).

Authors

Andrew I. Mikhail, Peter L. Nagy, Katherine Manta, Nicholas Rouse, Alexander Manta, Sean Y. Ng, Michael F. Nagy, Paul Smith, Jian-Qiang Lu, Joshua P. Nederveen, Vladimir Ljubicic, Mark A. Tarnopolsky

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Abstract

People living with HIV (PLWH) who are Immune Non-Responders (INR) persons are at greater risk of comorbidity and mortality than are Immune Responders (IR) who restore their CD4 T cells count (IR) after anti-retroviral therapy (ART). INR have low CD4-T cell counts (<350 c/ul), heightened systemic inflammation, and increased CD4-T cell cycling (Ki67+). Here we report the findings that memory CD4-T cells and plasma samples of INR from several cohorts are enriched in gut-derived bacterial solutes (GDBS) p-cresol-sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4-T cell counts. In vitro PCS or IS blocked CD4-T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging (EMI) revealed perturbations of mitochondria networks similar to those found in INR following incubation of healthy memory CD4-T cells with PCS. Using the bacterial 16S rDNA, INR stool samples were found enriched with proteolytic bacterial genera that metabolize tyrosine and phenylalanine amino acids to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4-T cell recovery during ART and may contribute to CD4-T cell lymphopenia characteristic of INR.

Authors

Brian Ferrari, Amanda Cabral Da Silva, Ken H. Liu, Evgeniya V. Saidakova, Larisa B. Korolevskaya, Konstantin V. Shmagel, Carey Shive, Gabriela Pacheco Sanchez, Mauricio Retuerto, Ashish Arunkumar Sharma, Khader Ghneim, Laura Noel-Romas, Benigno Rodriguez, Mahmoud A. Ghannoum, Peter P. Hunt, Steven G. Deeks, Adam D. Burgener, Dean P. Jones, Mirela A. Dobre, Vincent C. Marconi, Rafick-Pierre Sekaly, Souheil-Antoine Younes

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Abstract

The synthesis of serine from glucose is a key metabolic pathway supporting cellular proliferation in healthy and malignant cells. Despite this, the role that this aspect of metabolism plays in germinal center biology and pathology is not known. Here, we performed a comprehensive characterization of the role of the serine synthesis pathway in germinal center B cells and lymphomas derived from these cells. We demonstrated that upregulation of a functional serine synthesis pathway is a metabolic hallmark of B-cell activation and the germinal center reaction. Inhibition of phosphoglycerate dehydrogenase (PHGDH), the first and rate limiting enzyme in this pathway, led to defective germinal formation and impaired high-affinity antibody production. In addition, overexpression of enzymes involved in serine synthesis was a characteristic of germinal center B-cell derived lymphomas, with high levels of expression being predictive of reduced overall survival in diffuse large B cell lymphoma. Inhibition of PHGDH induced apoptosis in lymphoma cells reducing disease progression. These findings establish PHGDH as a critical player in humoral immunity and a clinically relevant target in lymphoma.

Authors

Annalisa D'Avola, Nathalie Legrave, Mylène Tajan, Probir Chakravarty, Ryan L. Shearer, Hamish W. King, Katarina Kluckova, Eric C. Cheung, Andrew J. Clear, Arief S. Gunawan, Lingling Zhang, Louisa K. James, James I. MacRae, John G. Gribben, Dinis P. Calado, Karen H. Vousden, John C. Riches

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Abstract

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human PD-1+Tim-3+ CD8+ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3+ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen-specific CD8+ T cells and PD-1+Tim-3+ CD8+ TILs isolated from melanoma patients. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8+ TILs in two melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not on CD8+ T cells impeded the trogocytosis of CD8+ TILs in vivo. Trogocytosed CD8+ T cells presented tumor peptide-major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism used by Tim-3 to limit antitumor immunity.

Authors

Ornella Pagliano, Robert M. Morrison, Joe-Marc Chauvin, Hridesh Banerjee, Diwakar Davar, Quanquan Ding, Tokiyoshi Tanegashima, Wentao Gao, Saranya Rani Chakka, Richelle DeBlasio, Ava Lowin, Kevin Kara, Mignane Ka, Bochra Zidi, Rada Amin, Itay Raphael, Shuowen Zhang, Simon C. Watkins, Cindy Sander, John M. Kirkwood, Marcus Bosenberg, Ana C. Anderson, Vijay K. Kuchroo, Lawrence P. Kane, Alan J. Korman, Arvind Rajpal, Sean M. West, Minhua Han, Christine Bee, Xiaodi Deng, Xiao Min Schebye, Pavel Strop, Hassane M. Zarour

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March 2022 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

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Review Series - More

New Therapeutic Targets in Cardiovascular Diseases

Series edited by Daniel P. Kelly

Cardiovascular diseases remain a leading cause of death worldwide, and treatment is complicated by the inadequacies of available therapies. This collection of reviews, developed by Daniel P. Kelly, explores emerging strategies for treating a range of cardiac pathologies, including: recent discoveries of epigenetic regulators that can be targeted to combat cardiac fibrosis, state of the art in genome-editing therapies, interactions of the vascular endothelium with metabolic tissues, current understanding of myosin modulators, and novel targets for treating dyslipidemia. Together, the reviews provide a broad update on numerous advances in cardiovascular medicine.

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Conversations with Giants in Medicine - More

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