ABSTRACT
BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a newly recognized condition affecting children with recent infection or exposure to coronavirus disease 2019 (COVID-19). MIS-C has symptoms that affect multiple organs systems, with some clinical features resembling Kawasaki disease (KD) and toxic shock syndrome (TSS). OBJECTIVE OF THE REVIEW: Our goal was to review the current literature and describe the evaluation and treatment algorithms for children suspected of having MIS-C who present to the emergency department. DISCUSSION: MIS-C has a wide clinical spectrum and diagnosis is based on a combination of both clinical and laboratory findings. The exact mechanism of immune dysregulation of MIS-C is not well understood. Physical findings may evolve and do not necessarily appear at the same time. Gastrointestinal, cardiac, inflammatory, and coagulopathy manifestations and dysfunction are seen frequently in MIS-C. CONCLUSIONS: The diagnosis of MIS-C is based on clinical presentation and specific laboratory findings. In the emergency setting, a high level of suspicion for MIS-C is required in patients exposed to COVID-19. Early diagnosis and prompt initiation of therapy offer the best chance for optimal outcomes.
Subject(s)
COVID-19 , Mucocutaneous Lymph Node Syndrome , COVID-19/complications , Child , Humans , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/etiologyABSTRACT
Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαß+CD4-CD8-NK1.1- innate αß T cells (iαßT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαßTs represent â¼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαßTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαßTs comprised â¼75% of the total intratumoral IL17+ cells. Moreover, iαßT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαßT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαßTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαßTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαßTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.See related commentary by Banerjee et al., p. 1164.This article is highlighted in the In This Issue feature, p. 1143.
Subject(s)
Carcinoma, Pancreatic Ductal/immunology , Macrophages/immunology , Pancreatic Neoplasms/immunology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , T-Lymphocytes/immunology , Animals , Carcinoma, Pancreatic Ductal/therapy , Cell Line, Tumor , Female , Humans , Immunity, Innate , Immunotherapy, Adoptive , Male , Mice , Mice, Inbred C57BL , Neoplasm Transplantation , Pancreatic Neoplasms/therapy , T-Lymphocytes/transplantation , Tumor MicroenvironmentABSTRACT
We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.
Subject(s)
Carcinogenesis , Microbiota , Monocytes/physiology , Pancreatic Neoplasms/microbiology , Toll-Like Receptors/metabolism , Animals , Bacteria , Cell Differentiation , Female , Humans , Male , Mice , Monocytes/immunology , Monocytes/metabolism , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/pathology , Signal TransductionABSTRACT
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
Subject(s)
Carcinoma, Pancreatic Ductal/immunology , Immune Tolerance/immunology , Macrophages/immunology , Pancreatic Neoplasms/immunology , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Humans , Immune Tolerance/genetics , L Cells , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Receptor-Interacting Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , STAT1 Transcription Factor/metabolism , Th1 Cells/cytology , Th17 Cells/cytologyABSTRACT
The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
Subject(s)
Adaptive Immunity , Macrophages/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Signal Transduction , Animals , Apoptosis Regulatory Proteins/deficiency , Apoptosis Regulatory Proteins/metabolism , CARD Signaling Adaptor Proteins , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Caspase 1/deficiency , Caspase 1/metabolism , Cell Differentiation , Cell Proliferation , Cellular Reprogramming , Gene Deletion , Humans , Immunosuppression Therapy , Mice, Inbred C57BL , Nod2 Signaling Adaptor Protein/metabolism , Pancreatic Stellate Cells/metabolism , Pancreatic Stellate Cells/pathology , T-Lymphocytes/immunology , Tumor Microenvironment , Pancreatic NeoplasmsABSTRACT
The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.