Immunology
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%–40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODS We performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTS In human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSION Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDING This work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.
Authors
Max Heiduk, Ioana Plesca, Jessica Glück, Luise Müller, David Digomann, Charlotte Reiche, Janusz von Renesse, Rahel Decker, Christoph Kahlert, Ulrich Sommer, Daniela E. Aust, Marc Schmitz, Jürgen Weitz, Lena Seifert, Adrian M. Seifert
Abstract
We determined whether gut microbiota-produced trimethylamine (TMA) is oxidized into trimethylamine N-oxide (TMAO) in non-liver tissues, whether TMAO promotes inflammation via trained immunity (TI) and made the following findings: Endoplasmic reticulum (ER) stress genes were co-upregulated with mitoCarta genes in chronic kidney diseases (CKD); TMAO upregulated 190 genes in human aortic endothelial cells (HAECs); TMAO synthesis enzyme flavin-containing monooxygenase 3 (FMO3) was expressed in human and mouse aortas,;4) TMAO trans-differentiated HAECs into innate immune cells; TMAO phosphorylated 12 kinases in cytosol via its receptor PERK and CREB, and integrated with PERK pathways; and PERK inhibitors suppressed TMAO-induced ICAM-1; TMAO upregulated 3 mitochondrial genes and downregulated inflammation inhibitor DARS2, induced mitoROS; and mitoTEMPO inhibited TMAO-induced ICAM-1; and -glucan priming followed by TMAO re-stimulation upregulated TNF-α by inducing metabolic reprogramming; and glycolysis inhibitor suppressed TMAO-induced ICAM-1. Our results have provided novel insights over TMAO roles in inducing EC activation and innate immune trans-differentiation, inducing metabolic reprogramming and TI for enhanced vascular inflammation and new therapeutic targets for treating cardiovascular diseases (CVD), CKD-promoted CVD, inflammations, transplantation, aging, and cancers.
Authors
Fatma Saaoud, Lu Liu, Keman Xu, Ramon Cueto, Ying Shao, Yifan Lu, Yu Sun, Nathaniel W. Snyder, Sheng Wu, Ling Yang, Yan Zhou, David L. Williams, Chuanfu Li, Laisel Martinez, Roberto I. Vazquez-Padron, Huaqing Zhao, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
Abstract
Despite the widespread use of SARS-CoV-2-specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2-specific T cell responses has been unknown, resulting in uncertainty as to whether anti-SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2-specific mAb may enhance adaptive immunity to SARS-CoV-2 via a "vaccinal effect." Bamlanivimab (Eli Lilly) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2 specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with 700 mg bamlanivimab versus placebo. SARS-CoV-2-specific T cell responses were evaluated using activation induced marker (AIM) assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 develop SARS-CoV-2-specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2-specific T cell memory was robust in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2-specific cellular immunity.
Authors
Sydney I. Ramirez, Alba Grifoni, Daniela Weiskopf, Urvi M. Parikh, Amy Heaps, Farhoud Faraji, Scott F. Sieg, Justin Ritz, Carlee B. Moser, Joseph J. Eron, Judith S. Currier, Paul Klekotka, Alessandro Sette, David A. Wohl, Eric S. Daar, Michael D. Hughes, Kara W. Chew, Davey M. Smith, Shane Crotty
Abstract
Glucocorticoids remain a cornerstone of therapeutic regimes for autoimmune and chronic inflammatory diseases, for example, in different forms of crescentic glomerulonephritis because of their rapid anti-inflammatory effects, low cost, and wide availability. Despite their routine use for decades, the underlying cellular mechanisms by which steroids exert their therapeutic effects need to be fully elucidated. Here, we demonstrate that high-dose steroid treatment rapidly reduced the number of proinflammatory CXCR3+ CD4+ T cells in the kidney by combining high-dimensional single-cell and morphological analyses of kidney biopsies from patients with antineutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis. Using an experimental model of crescentic glomerulonephritis, we show that the steroid-induced decrease in renal CD4+ T cells is a consequence of reduced T-cell recruitment, which is associated with an ameliorated disease course. Mechanistic in vivo and in vitro studies revealed that steroids act directly on renal tissue cells, such as tubular epithelial cells, but not on T cells, which resulted in an abolished renal expression of CXCL9 and CXCL10, as well as in the prevention of CXCR3+ CD4+ T-cell recruitment to the inflamed kidneys. Thus, we identified the CXCL9/10-CXCR3 axis as a previously unrecognized cellular and molecular target of glucocorticoids providing protection from immune-mediated pathology.
Authors
Jan-Hendrik Riedel, Lennart Robben, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Ning Song, Anett Peters, Anna Kaffke, Alina C. Borchers, Gisa Tiegs, Larissa Seifert, Nicola M. Tomas, Elion Hoxha, Ulrich O. Wenzel, Tobias B. Huber, Thorsten Wiech, Jan-Eric Turner, Christian F. Krebs, Ulf Panzer
Abstract
Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis–associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis–associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications — TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.
Authors
Nathan Richoz, Zewen K. Tuong, Kevin W. Loudon, Eduardo Patiño-Martínez, John R. Ferdinand, Anaïs Portet, Kathleen R. Bashant, Emeline Thevenon, Francesca Rucci, Thomas Hoyler, Tobias Junt, Mariana J. Kaplan, Richard M. Siegel, Menna R. Clatworthy
Abstract
Human NK cell deficiency (NKD) is a primary immunodeficiency in which the main clinically relevant immunological defect involves missing or dysfunctional NK cells. Here, we describe a familial NKD case in which 2 siblings had a substantive NKD and neutropenia in the absence of other immune system abnormalities. Exome sequencing identified compound heterozygous variants in Go-Ichi-Ni-San (GINS) complex subunit 4 (GINS4, also known as SLD5), an essential component of the human replicative helicase, which we demonstrate to have a damaging impact upon the expression and assembly of the GINS complex. Cells derived from affected individuals and a GINS4-knockdown cell line demonstrate delayed cell cycle progression, without signs of improper DNA synthesis or increased replication stress. By modeling partial GINS4 depletion in differentiating NK cells in vitro, we demonstrate the causal relationship between the genotype and the NK cell phenotype, as well as a cell-intrinsic defect in NK cell development. Thus, biallelic partial loss-of-function mutations in GINS4 define a potentially novel disease-causing gene underlying NKD with neutropenia. Together with the previously described mutations in other helicase genes causing NKD, and with the mild defects observed in other human cells, these variants underscore the importance of this pathway in NK cell biology.
Authors
Matilde I. Conte, M. Cecilia Poli, Angelo Taglialatela, Giuseppe Leuzzi, Ivan K. Chinn, Sandra A. Salinas, Emma Rey-Jurado, Nixa Olivares, Liz Veramendi-Espinoza, Alberto Ciccia, James R. Lupski, Juan Carlos Aldave Becerra, Emily M. Mace, Jordan S. Orange
Abstract
Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first post-transplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. Natural killer (NK) cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. Together, these data support an aberrant NK cell-neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.
Authors
Daniel R. Calabrese, Tasha Tsao, Mélia Magnen, Colin Valet, Ying Gao, Beñat Mallavia, Jennifer J. Tian, Emily A. Aminian, Kristin M. Wang, Avishai Shemesh, Elman B. Punzalan, Aartik Sarma, Carolyn S. Calfee, Stephanie A. Christenson, Charles R. Langelier, Steven R. Hays, Jeff A. Golden, Lorriana E. Leard, Mary E. Kleinhenz, Nicholas A. Kolaitis, Rupal J. Shah, Aida Venado, Lewis L. Lanier, John R. Greenland, David M. Sayah, Abbas Ardehali, Jasleen Kukreja, S. Sam Weigt, John A. Belperio, Jonathan P Singer, Mark R. Looney
Abstract
Pancreatic neuroendocrine tumors (PNETs) are malignancies arising from the islets of Langerhans. Therapeutic options are limited for the over 50% of patients who present with metastatic disease. We aimed to identify mechanisms to remodel the PNET tumor microenvironment (TME) to ultimately enhance susceptibility to immunotherapy. The TMEs of localized and metastatic PNETs were investigated using an approach that combines RNA-sequencing, cancer and T cell profiling, and pharmacologic perturbations. RNA-sequencing analysis indicated that the primary tumors of metastatic PNETs showed significant activation of inflammatory and immune-related pathways. We determined that metastatic PNETs featured increased numbers of tumor-infiltrating T cells compared to localized tumors. T cells isolated from both localized and metastatic PNETs showed evidence of recruitment and antigen-dependent activation, suggestive of an immune-permissive microenvironment. A computational analysis suggested that vorinostat, a histone deacetylase inhibitor, may perturb the transcriptomic signature of metastatic PNETs. Treatment of PNET cell lines with vorinostat increased chemokine CCR5 expression by NF-κB activation. Vorinostat treatment of patient-derived metastatic PNET tissues augmented recruitment of autologous T cells, which was substantiated in a mouse model of PNET. Pharmacologic induction of chemokine expression may represent a promising approach for enhancing the immunogenicity of metastatic PNET TMEs.
Authors
Jacques Greenberg, Jessica Limberg, Akanksha Verma, David Kim, Xiang Chen, Yeon J. Lee, Maureen D. Moore, Timothy M. Ullmann, Jessica W. Thiesmeyer, Zachary Loewenstein, Kevin J. Chen, Caitlin E. Egan, Dessislava Stefanova, Rohan Bareja, Rasa Zarnegar, Brendan M. Finnerty, Theresa Scognamiglio, Yi-Chieh Nancy Du, Olivier Elemento, Thomas J. Fahey III, Irene M. Min
Abstract
Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use yet whether the immunologic effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti-IL-6 (siltuximab) or anti-IL-6 receptor (IL-6R; tocilizumab) and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced IL-6-driven STAT3 phosphorylation, ICOS expression on T follicular helper cell populations and TCR-driven STAT3 phosphorylation. Siltuximab reversed resistance to regulatory T cell-mediated suppression and increased TCR driven pSTAT3, and production of IL-10, IL-21 and IL-27 by T effectors. Together these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell intrinsic changes that may influence therapeutic outcomes.
Authors
Cate Speake, Tania Habib, Katharina Lambert, Christian Hundhausen, Sandra Lord, Matthew J. Dufort, Samuel O. Skinner, Alex Hu, MacKenzie Kinsman, Britta E. Jones, Megan D. Maerz, Megan Tatum, Anne M. Hocking, Gerald T. Nepom, Carla J. Greenbaum, Jane H. Buckner
Abstract
Peritoneal metastases are associated with a low response rate to immune checkpoint blockade (ICB) therapy. The numbers of peritoneal resident macrophages (PRMs) are reversely correlated with the response rate to ICB therapy. We have previously shown that TLR9 in fibroblastic reticular cells (FRCs) plays a critical role in regulating peritoneal immune cell recruitment. However, the role of TLR9 in FRCs in regulating PRMs is unclear. Here, we demonstrated that the class A TLR9 agonist, ODN1585, markedly enhanced the efficacy of anti–PD-1 therapy in mouse models of colorectal peritoneal metastases. ODN1585 injected i.p. reduced the numbers of Tim4+ PRMs and enhanced CD8+ T cell antitumor immunity. Mechanistically, treatment of ODN1585 suppressed the expression of genes required for retinoid metabolism in FRCs, and this was associated with reduced expression of the PRM lineage–defining transcription factor GATA6. Selective deletion of TLR9 in FRCs diminished the benefit of ODN1585 in anti–PD-1 therapy in reducing peritoneal metastases. The crosstalk between PRMs and FRCs may be utilized to develop new strategies to improve the efficacy of ICB therapy for peritoneal metastases.
Authors
Ting Jiang, Hongji Zhang, Yiming Li, Preethi Jayakumar, Hong Liao, Hai Huang, Timothy R. Billiar, Meihong Deng
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