ABSTRACT
The drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-ß, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103- DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.
Subject(s)
Dendritic Cells/immunology , Interleukin-10/metabolism , Interleukin-17/metabolism , Pancreatic Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Adenocarcinoma/genetics , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Animals , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/immunology , Carcinoma, Pancreatic Ductal/pathology , Cell Differentiation , Disease Progression , Forkhead Transcription Factors , Gene Expression Regulation, Neoplastic , Humans , Lectins, C-Type/metabolism , Mice, Inbred C57BL , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Phenotype , Signal Transduction , Th17 Cells/immunology , Toll-Like Receptor 2/metabolism , Tretinoin/metabolism , Pancreatic NeoplasmsABSTRACT
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.