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Hyperglycemia cooperates with Tet2 heterozygosity to induce leukemia driven by pro-inflammatory cytokine induced lncRNA Morrbid

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Abstract

Diabetes mellitus (DM) is a risk factor for cancer development. However, the role of DM induced hyperglycemic stress (HG) in the development of blood cancer is poorly understood, largely due to lack of appropriate animal models. Epidemiologic studies show that individuals with DM are more likely to possess higher rate of mutations in genes found in pre-leukemic stem and progenitor cells (pre-LHSC/Ps) including in the epigenetic regulator TET2. TET2-mutant pre-LHSC/Ps require additional hits to evolve into a full-blown leukemia and/or aggressive myeloproliferative neoplasm (MPN). Cell intrinsic mutations have been shown to cooperate with Tet2 to promote leukemic transformation. However, the role of extrinsic factors is poorly understood. Utilizing a novel mouse model bearing haploinsufficiency of Tet2, to mimic the human pre-LHSC/P condition and HG stress, in the form of an Ins2Akita/+ mutation, which induces HG and Type-1 DM, we show that the compound mutant mice develop a lethal form of MPN and/or acute myeloid leukemia (AML). RNAseq revealed that this is in part due to upregulation of pro-inflammatory pathways, thereby generating a feedforward loop, including the expression of an anti-apoptotic lncRNA Morrbid. Loss of Morrbid in the compound mutants rescues the lethality and mitigates the development of MPN/AML. Our results describe a novel mouse model for age-dependent AML/MPN and suggest that HG stress acts as an environmental driver for myeloid neoplasm, which could be effectively prevented by reducing the expression of inflammation-related lncRNA Morrbid.

Authors

Zhigang Cai, Xiaoyu Lu, Chi Zhang, Sai Nelanuthala, Fabiola Aguilera, Abigail Hadley, Baskar Ramdas, Fang Fang, Kenneth P. Nephew, Jonathan J. Kotzin, Adam Williams, Jorge Henao-Mejia, Laura S. Haneline, Reuben Kapur

Graft-versus-host disease depletes plasmacytoid dendritic cell progenitors to impair tolerance induction

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Abstract

Graft-versus-host disease (GVHD) causes failed reconstitution of donor plasmacytoid dendritic cells (pDCs) that are critical for immune protection and tolerance. We used both murine and human systems to uncover the mechanisms whereby GVHD induces donor pDC defects. GVHD depleted Flt3-expressing donor multipotent progenitors (MPPs) that sustained pDCs, leading to impaired generation of pDCs. MPP loss was associated with decreased amounts of MPP-producing hematopoietic stem cells (HSCs) and oxidative stress-induced death of proliferating MPPs. Additionally, alloreactive T cells produced GM-CSF to inhibit MPP expression of Tcf4, the transcription factor essential for pDC development, subverting MPP production of pDCs. GM-CSF did not affect the maturation of pDC precursors. Notably, enhanced recovery of donor pDCs upon adoptive transfer early after allogeneic HSC transplantation repressed GVHD and restored the de novo generation of donor pDCs in recipient mice. pDCs suppressed the proliferation and expansion of activated autologous T cells via a type-I IFN signaling-dependent mechanism. They also produced PD-L1 and LILRB4 to inhibit T cell production of IFN-. We thus demonstrate that GVHD impairs the reconstitution of tolerogenic donor pDCs by depleting DC progenitors rather than by preventing pDC maturation. MPPs are an important target to effectively bolster pDC reconstitution for controlling GVHD.

Authors

Yuanyuan Tian, Lijun Meng, Ying Wang, Bohan Li, Hongshuang Yu, Yan Zhou, Tien Bui, Alicia Li, Ciril Abraham, Yongping Zhang, Jian Wang, Chenchen Zhao, Shin Mineishi, Stefania Gallucci, David Porter, Elizabeth Hexner, Hong Zheng, Yanyun Zhang, Shaoyan Hu, Yi Zhang

Age-related susceptibility to Coronavirus infections: role of impaired and dysregulated host immunity

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Abstract

Human coronaviruses (hCoVs) cause severe respiratory illness in the elderly. Age-related impairments in innate immunity and sub-optimal virus-specific T cell and antibody responses are believed to cause severe disease upon respiratory virus infections. This phenomenon has recently received increased attention, as elderly patients are at substantially elevated risk for severe COVID-19 disease and experience increased rates of mortality following SARS-CoV-2 infection compared to younger populations. However, the basis for age-related fatal pneumonia following pathogenic hCoVs is not well understood. In this review article, we provide an overview of our current understanding of hCoV-induced fatal pneumonia in the elderly. We describe host immune response to hCoV infections derived from studies of young and aged animal models, and discuss the potential role of age-associated increases in sterile inflammation (inflammaging) and virus-induced dysregulated inflammation in causing age-related severe disease. We also highlight the existing gaps in our knowledge about virus replication and host immune responses to hCoV infection in young and aged individuals..

Authors

Rudragouda Channappanavar, Stanley Perlman

CLIC1 recruits PIP5K1A/C to induce cell-matrix adhesions for tumor metastasis

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Abstract

Membrane protrusion and adhesion to the extracellular matrix, which involves the extension of actin filaments and formation of adhesion complexes, are the fundamental processes for cell migration, tumor invasion, and metastasis. How cancer cells efficiently coordinate these processes remains unclear. Here, we showed that membrane-targeted CLIC1 spatiotemporally regulates the formation of cell-matrix adhesions and membrane protrusions through the recruitment of PIP5Ks to the plasma membrane. Comparative proteomics identified CLIC1 upregulated in human hepatocellular carcinoma (HCC) and associated with tumor invasiveness, metastasis, and poor prognosis. In response to migration-related stimuli, CLIC1 recruited PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane, where PIP5Ks generate a PIP2-rich microdomain to induce the formation of integrin-mediated cell-matrix adhesions and the signaling for cytoskeleon extension. CLIC1 silencing inhibited the attachment of tumor cells to culture plates and the adherence and extravasation in the lung alveoli resulting in suppressed lung metastasis in mice. This study reveals an unrecognized mechanism that spatiotemporally coordinates the formation of both lamellipodium/invadopodia and nascent cell-matrix adhesions for directional migration and tumor invasion/metastasis. The unique traits of upregulation and membrane targeting of CLIC1 in cancer cells make it an excellent therapeutic target for tumor metastasis.

Authors

Jei-Ming Peng, Sheng-Hsuan Lin, Ming-Chin Yu, Sen-Yung Hsieh

Guanosine triphosphate links MYC-dependent metabolic and ribosome programs in small cell lung cancer

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Abstract

MYC stimulates both metabolism and protein synthesis, but it is unknown how cells coordinate these complementary programs. Previous work reported that in a subset of small cell lung cancer (SCLC) cell lines, MYC activates guanosine triphosphate (GTP) synthesis and results in sensitivity to inhibitors of the GTP synthesis enzyme inosine monophosphate dehydrogenase (IMPDH). Here we demonstrated that primary MYCHigh human SCLC tumors also contain abundant guanosine nucleotides. We also found that elevated MYC in SCLCs with acquired chemoresistance rendered these otherwise recalcitrant tumors dependent on IMPDH. Unexpectedly, our data indicated that IMPDH links the metabolic and protein synthesis outputs of oncogenic MYC. Co-expression analysis placed IMPDH within the MYC-driven ribosome program, and GTP depletion prevented RNA Polymerase I (Pol I) from localizing to ribosomal DNA. Furthermore, the GTPases GPN1 and GPN3 were upregulated by MYC and directed Pol I to ribosomal DNA. Constitutively GTP-bound GPN1/3 mutants mitigated the effect of GTP depletion on Pol I, protecting chemoresistant SCLC cells from IMPDH inhibition. GTP therefore functions as a metabolic gate tethering MYC-dependent ribosome biogenesis to nucleotide sufficiency through GPN1 and GPN3. IMPDH dependence is a targetable vulnerability in chemoresistant, MYCHigh SCLC.

Authors

Fang Huang, Kenneth Huffman, Zixi Wang, Xun Wang, Kailong Li, Feng Cai, Chendong Yang, Ling Cai, Terry S. Shih, Lauren G. Zacharias, Andrew S. Chung, Qian Yang, Milind D. Chalishazar, Abbie S. Ireland, C. Allison Stewart, Kasey R. Cargill, Luc Girard, Yi Liu, Min Ni, Jian Xu, Xudong Wu, Hao Zhu, Benjamin J. Drapkin, Lauren A. Byers, Trudy G. Oliver, Adi Gazdar, John Minna, Ralph DeBerardinis

Lung megakaryocytes are immune modulatory cells

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Abstract

While platelets are the cellular mediators of thrombosis, platelets are also immune cells. Platelets interact both directly and indirectly with immune cells, impacting their activation and differentiation, as well as all phases of the immune response. Megakaryocytes (Mks) are the cell source of circulating platelets, and until recently Mks were typically only considered as bone marrow (BM) resident cells. However, platelet producing Mks also reside in the lung, and lung Mks express greater levels of immune molecules compared to BM Mks. We therefore sought to define the immune functions of lung Mks. Using single cell RNA-Seq of BM and lung myeloid enriched cells, we found that lung Mks (MkL) had gene expression patterns that are similar to antigen presenting cells (APC). This was confirmed using imaging and conventional flow cytometry. The immune phenotype of Mks was plastic and driven by the tissue immune environment as evidenced by BM Mks having a MkL like phenotype under the influence of pathogen receptor challenge and lung associated immune molecules, such as IL-33. Our in vitro and in vivo assays demonstrated that MkL internalized and processed both antigenic proteins and bacterial pathogens. Furthermore, MkL induced CD4+ T cell activation in a MHC II dependent manner both in vitro and in vivo. These data indicated that Mks in the lung had key immune regulatory roles dictated in part by the tissue environment.

Authors

Daphne N. Pariser, Zachary T. Hilt, Sara K. Ture, Sara K. Blick-Nitko, Mark R. Looney, Simon J. Cleary, Estheany Roman-Pagan, Jerry Saunders II, Steve N. Georas, Janelle M. Veazey, Ferralita Madere, Laura Tesoro Santos, Allison M. Arne, Nguyen PT Huynh, Alison C. Livada, Selena M. Guerrero-Martin, Claire E. Lyons, Kelly A. Metcalf Pate, Kathleen E. McGrath, James Palis, Craig Morrell

SARS-CoV-2 specific antibody rearrangements in pre-pandemic immune repertoires of risk cohorts and COVID-19 patients

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Abstract

A considerable fraction of B cells recognize SARS-CoV-2 with germline-encoded elements of their B cell receptor resulting in the production of neutralizing and non-neutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts confirming the stereotyped character of this naive response in COVID-19. While neutralizing antibody sequences were found independently of disease severity in line with serological data, individual non-neutralizing antibody sequences were associated with fatal clinical courses suggesting detrimental effects of these antibodies. We mined 200 immune repertoires of healthy individuals and 500 of patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely found in individuals over 60 years of age and in cancer. This reflects B cell repertoire restriction in aging and cancer and may to a certain extent explain the different clinical COVID-19 courses observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.

Authors

Lisa Paschold, Donjete Simnica, Edith Willscher, Maria J.G.T. Vehreschild, Jochen Dutzmann, Daniel G. Sedding, Christoph Schultheiß, Mascha Binder

Galectin‐7 downregulation in lesional keratinocytes contributes to enhanced IL‐17A signaling and skin pathology in psoriasis

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Abstract

Psoriasis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration, as well as hyperproliferation of keratinocytes in skin lesions, and is considered a metabolic syndrome. We found that the expression of galectin-7 is reduced in the skin lesions of patients with psoriasis. IL-17A and TNF-α, two cytokines intimately involved in the development of psoriatic lesions, suppressed galectin-7 expression in human primary keratinocytes (HEKn cells) and the immortalized human keratinocyte cell line HaCaT. A galectin-7 knockdown in these cells elevated the production of IL-6 and IL-8 and enhanced ERK signaling when the cells were stimulated with IL-17A. Galectin-7 attenuated IL-17A–induced production of inflammatory mediators by keratinocytes via the miR-146a–ERK pathway. Moreover, galectin-7–deficient mice showed enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map (cMAP) analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validate a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulated a rationale for the use of statins in the treatment of psoriasis.

Authors

Hung-Lin Chen, Chia-Hui Lo, Chi-Chun Huang, Meng-Ping Lu, Po-Yuan Hu, Chang-Shan Chen, Di-Yen Chueh, Peilin Chen, Teng-Nan Lin, Yuan-Hsin Lo, Yu-Ping Hsiao, Daniel K. Hsu, Fu-Tong Liu

What are protective antibody responses to pandemic SARS-CoV-2?

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Abstract

Human antibody responses to severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) hold intense interest with research efforts directed at optimizing antibody-based interventions and monitoring immune status. By relating individual variations in antibody response to coronavirus disease 2019 (COVID-19) severity, beneficial antiviral immune responses may be identified in detail. In this issue of the JCI, Secchi and collaborators describe antibody response profiles in 509 COVID-19 patients from Italy during the 2020 pandemic. The research team found that multiple antibody types to multiple SARS-CoV-2 antigens developed over four weeks. Notably, IgG against the spike receptor binding domain (RBD) was predictive of survival and IgA against the viral spike protein (S protein) associated with rapid virologic clearance. These results may help guide selection of convalescent plasma, hyperimmune products, monoclonal antibodies, and vaccine strategies for COVID-19.

Authors

Jeffrey P. Henderson

Identification of human long non-coding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis

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Abstract

A growing number of long non-coding RNAs (lncRNAs) have emerged as vital metabolic regulators. However, most human lncRNAs are non-conserved and highly tissue-specific, vastly limiting our ability to identify human lncRNA metabolic regulators (hLMRs). In this study, we establish a pipeline to identify putative hLMRs that are metabolically sensitive, disease-relevant, and population applicable. We first progressively processed multilevel human transcriptome data to select liver lncRNAs that exhibit highly dynamic expression in the general population, show differential expression in a nonalcoholic fatty liver disease (NAFLD) population, and response to dietary intervention in a small NAFLD cohort. We then experimentally demonstrated the responsiveness of selected hepatic lncRNAs to defined metabolic milieus in a liver-specific humanized mouse model. Furthermore, by extracting a concise list of protein-coding genes that are persistently correlated with lncRNAs in general and NAFLD populations, we predicted the specific function for each hLMR. Using gain- and loss-of-function approaches in humanized mice as well as ectopic expression in conventional mice, we validated the regulatory role of one non-conserved hLMR in cholesterol metabolism by coordinating with an RNA-binding protein, PTBP1, to modulate the transcription of cholesterol synthesis genes. Our work overcome the heterogeneity intrinsic to human data to enable the efficient identification and functional definition of disease-relevant human lncRNAs in metabolic homeostasis.

Authors

Xiangbo Ruan, Ping Li, Yonghe Ma, Chengfei Jiang, Yi Chen, Yu Shi, Nikhil Gupta, Fayaz Seifuddin, Mehdi Pirooznia, Yasuyuki Ohnishi, Nao Yoneda, Megumi Nishiwaki, Gabrijela Dumbovic, John L. Rinn, Yuichiro Higuchi, Kenji Kawai, Hiroshi Suemizu, Haiming Cao

Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis

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Abstract

Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites (3’ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3’ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.

Authors

Bo Liu, Zhaoqi Liu, Sisi Chen, Michelle Ki, Caroline Erickson, Jorge S. Reis-Filho, Benjamin H. Durham, Qing Chang, Elisa de Stanchina, Yiwei Sun, Raul Rabadan, Omar Abdel-Wahab, Sarat Chandarlapaty

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

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Abstract

Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control for food intake and energy expenditure. Here we reported that, contrary to females, male mice lacking circadian nuclear receptors REV-ERB alpha and beta in the tuberal hypothalamus (HDKO) gained excessive weight on an obesogenic high fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HDKO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.

Authors

Marine Adlanmerini, Hoang C. B. Nguyen, Brianna M. Krusen, Clare W. Teng, Caroline E. Geisler, Lindsey C. Peed, Bryce J. Carpenter, Matthew R. Hayes, Mitchell A. Lazar

Ventromedial hypothalamic primary cilia control energy and skeletal homeostasis

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Abstract

Dysfunction of primary cilia is related to dyshomeostasis, leading to a wide range of disorders. The ventromedial hypothalamus (VMH) is known to regulate several homeostatic processes, but those modulated specifically by VMH-primary cilia are not yet known. In this study, we identify VMH-primary cilia as an important organelle that maintains energy and skeletal homeostasis by modulating the autonomic nervous system. We established loss-of-function models of primary cilia in the VMH by either targeting IFT88 (IFT88 KOSF-1) using steroidogenic factor 1-Cre (SF1-Cre) or injecting an adeno-associated virus Cre (AAV-Cre) directly into the VMH. Functional impairments of VMH-primary cilia were linked to decreased sympathetic activation and central leptin resistance, which led to marked obesity and bone density accrual. Obesity was caused by hyperphagia, decreased energy expenditure, and blunted brown fat function, as well as associated with insulin and leptin resistance. The effect of bone density accrual was independent from obesity, as it was caused by the decreased sympathetic tone resulting in increased osteoblastic and decreased osteoclastic activities in the IFT88 KOSF-1 and VMH-primary cilia knock-down mice. Overall, our current study identifies VMH-primary cilia as a critical hypothalamic organelle that maintains energy and skeletal homeostasis.

Authors

Ji Su Sun, Dong Joo Yang, Ann W. Kinyua, Seul Gi Yoon, Je Kyung Seong, Juwon Kim, Seok Jun Moon, Dong Min Shin, Yun-Hee Choi, Ki Woo Kim

Promoting the success of women and minority physician-scientists in academic medicine: a dean’s perspective

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Abstract

Dr. Nancy Brown, Dean of the Yale School of Medicine, shares her perspective on the challenges facing women and minority faculty members and trainees in academic medicine and provides a reflection on how leaders in academic medicine can promote diversity, equity, and inclusion to enhance their success.

Authors

Nancy J. Brown

COVID-19 and myeloid cells: complex interplay correlates with lung severity

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Abstract

COVID-19 spans and wide range of symptoms, sometimes with profound immune system involvement. How immune cell subsets change during the disease course and with disease severity needs further study. While myeloid cells have been shown to initiate and maintain responses to pneumonia and lung inflammation, often playing a role in resolution, their involvement with COVID-19 remains unknown. In this issue of the JCI, Sánchez-Cerrillo and Pedro-Landete et al. investigated dendritic cells and monocytes from blood and bronchial secretions of patients with varying COVID-19 severity and with healthy controls. The authors conclude that circulating monocytes and DCs migrate from the blood into the inflamed lungs. While sampling differences in sex, collection timing, bacteria/fungal infection, and corticosteroid treatment limit interpretation, we believe that reprograming monocyte or macrophages by targeting immunometabolism, epigenetics, or the cytokine milieu holds promise in resolving lung-inflammation associated with COVID-19.

Authors

Franco R. D'Alessio, Nicola M. Heller

Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing

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Abstract

BACKGROUND. Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS. One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) clinical site from 2014-2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS. The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen-de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSION. For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA.

Authors

David R. Murdock, Hongzheng Dai, Lindsay C. Burrage, Jill A. Rosenfeld, Shamika Ketkar, Michaela F. Müller, Vicente A. Yépez, Julien Gagneur, Pengfei Liu, Shan Chen, Mahim Jain, Gladys Zapata, Carlos A. Bacino, Hsiao-Tuan Chao, Paolo Moretti, William J. Craigen, Neil A. Hanchard, Brendan Lee

Protein tyrosine phosphatase non-receptor type 2 controls colorectal cancer development

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Abstract

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) recently emerged as a promising cancer immunotherapy target. We set to investigate the functional role of PTPN2 in the pathogenesis of human colorectal carcinoma (CRC) as its role in immune-silent solid tumors is poorly understood. We demonstrate that in human CRC, increased PTPN2 expression and activity correlated with disease progression and decreased immune responses in tumor tissues. Particularly, stage II and III tumors displayed enhanced PTPN2 protein expression in tumor-infiltrating T-cells and increased PTPN2 levels negatively correlated with PD1, CTLA4, STAT1 and granzyme A. In vivo, T-cell and dendritic cell-specific PTPN2 deletion reduced tumor burden in several CRC models by promoting CD44+ effector/memory T-cells, as well as CD8+ T-cell infiltration and cytotoxicity into the tumor. In direct relevance to CRC treatment, T-cell-specific PTPN2 deletion potentiated anti-PD-1 efficacy and induced anti-tumor memory formation upon tumor re-challenge in vivo. Our data suggest a role for PTPN2 in suppressing anti-tumor immunity and promoting tumor development in CRC patients. Our in vivo results uncover PTPN2 as a key player in controlling immunogenicity of CRC, with the strong potential to be exploited to promote cancer immunotherapy.

Authors

Egle Katkeviciute, Larissa Hering, Ana Montalban-Arques, Philipp Busenhart, Marlene Schwarzfischer, Roberto Manzini, Javier Conde, Kirstin Atrott, Silvia Lang, Gerhard Rogler, Elisabeth Naschberger, Vera S. Schellerer, Michael Stürzl, Andreas Rickenbacher, Matthias Turina, Achim Weber, Sebastian Leibl, Gabriel E. Leventhal, Mitchell Levesque, Onur Boyman, Michael Scharl, Marianne R. Spalinger

Recent endemic coronavirus infection is associated with less severe COVID-19

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Abstract

Four different endemic coronaviruses (eCoVs) are etiologic agents for the seasonal “common cold,” and these eCoVs share extensive sequence homology with human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we show that individuals with as compared to without a relatively recent documented eCoV were tested at greater frequency for respiratory infections but had similar rate of SARS-CoV-2 acquisition. Importantly, the patients with a previously detected eCoV had less severe coronavirus disease-2019 (COVID-19) illness. Our observations suggest that pre-existing immune responses against endemic human coronaviruses can mitigate disease manifestations from SARS-CoV-2 infection.

Authors

Manish Sagar, Katherine Reifler, Michael Rossi, Nancy S. Miller, Pranay Sinha, Laura White, Joseph P. Mizgerd

COVID-19 survival associates with the immunoglobulin response to the SARS-CoV-2 spike Receptor Binding Domain

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Abstract

BACKGROUND. Serological assays are of critical importance to investigate correlates of response and protection in COVID-19, to define previous exposure to SARS-CoV-2 in populations and to verify the development of an adaptive immune response in infected individuals. METHODS. We studied 509 confirmed COVID-19 patients from the San Raffaele Hospital of Milan and 480 pre-pandemic organ donor sera collected in 2010-2012. Using fluid-phase luciferase immune precipitation (LIPS) assays, we characterized IgG, IgM, IgA antibodies to the spike Receptor Binding Domain (RBD), S1+S2, nucleocapsid, and ORF6 to 10 of SARS-CoV-2, to the HCoV-OC43 and HCoV-HKU1 betacoronaviruses spike S2, and the H1N1Ca2009 flu virus hemagglutinin. Sequential samples at 1 and 3 months post-hospital discharge were also tested in 95 patients for SARS-CoV-2 RBD antibodies. RESULTS. Antibodies developed rapidly against multiple SARS-CoV-2 antigens in 95% of patients by 4 weeks post-symptoms onset and IgG to the RBD increased until the 3rd month of follow-up. We observed a major synchronous expansion of antibodies to the HCoV-OC43 and HCoV-HKU1 spike S2. A likely co-infection with influenza was neither linked to a more severe presentation of the disease nor to a worse outcome. Of the measured antibody responses positivity for IgG against the SARS-CoV-2 spike RBD was predictive of survival. CONCLUSIONS. The measurement of antibodies to selected epitopes of SARS-CoV-2 antigens can offer a more accurate assessment of the humoral response in patients and its impact on survival. The presence of partially cross-reactive antibodies with other betacoronoviruses is likely to impact on serological assay specificity and interpretation.

Authors

Massimiliano Secchi, Elena Bazzigaluppi, Cristina Brigatti, Ilaria Marzinotto, Cristina Tresoldi, Patrizia Rovere-Querini, Andrea Poli, Antonella Castagna, Gabriella Scarlatti, Alberto Zangrillo, Fabio Ciceri, Lorenzo Piemonti, Vito Lampasona

Endothelial C3a receptor mediates vascular inflammation and BBB permeability during aging

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Abstract

Dysfunction of immune and vascular systems has been implicated in aging and Alzheimer’s disease; however, their interrelatedness remains poorly understood. The complement pathway is a well-established regulator of innate immunity in the brain. Here, we report robust age-dependent increases in vascular inflammation, peripheral lymphocyte infiltration, and blood-brain barrier (BBB) permeability. These phenotypes were subdued by global inactivation and by endothelial-specific ablation of C3ar1. Using an in vitro model of the BBB, we identify intracellular Ca2+ as a downstream effector of C3a-C3aR signaling and a functional mediator of VE-cadherins junction and barrier integrity. Endothelial C3ar1 inactivation also dampened microglia reactivity and improved hippocampal and cortical volumes in the aging brain, demonstrating a crosstalk between brain vasculature dysfunction and immune cell activation and neurodegeneration. Further, prominent C3aR-dependent vascular inflammation is also observed in a tau transgenic mouse model. Our studies suggest that heightened C3a-C3aR signaling through endothelial cells promotes vascular inflammation and BBB dysfunction and contribute to overall neuroinflammation in aging and neurodegenerative disease.

Authors

Nicholas E. Propson, Ethan R. Roy, Alexandra Litvinchuk, Jorg Köhl, Hui Zheng