CCR1 drives immunosuppressive properties of tumor associated macrophages in pancreatic cancer
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PROVIDER: PRJNA1120471 | ENA |
REPOSITORIES: ENA
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Project description:Immunotherapy approaches have been ineffective in pancreatic ductal adenocarcinoma (PDA), pointing to the need for additional avenues to target in the pancreatic cancer microenvironment. We previously discovered that tumor educated bone marrow derived macrophages express high levels of C-C Motif Chemokine Receptor 1 (CCR1). By single-cell RNA sequencing, we found CCR1 to be expressed predominantly by tumor associated macrophages (TAMs) and granulocytes in both human and mouse PDA. Thus, we sought to investigate the functional role of CCR1 in pancreatic cancer. Using KC; Ccr1-/- mice (Ptf1a-Cre; LSL-KrasG12D; Ccr1-/-), we determined that CCR1 is dispensable during pancreatic cancer initiation, although we observed increased CD8 T cell infiltration in KC; Ccr1-/- pancreata. Using syngeneic orthotopic PDA mouse models we discovered that CCR1 ablation in Ccr1-/- mice or pharmaceutical inhibition of CCR1 both resulted in reduced tumor growth. Further, CCR1 ablation prolonged the overall survival of KPC mice. Through mass cytometry (CyTOF) and co-immunofluorescence staining we showed CCR1 ablation elevated CD8 T cell cytotoxic activity in the orthotopic PDA model. Mechanistically we found TAMs lacking CCR1 expressed less Arginase 1 and CD206 -both immunosuppressive markers of macrophages- compared to wild type TAMs. Further, targeting both CCR1 and Arginase 1 synergized with immune checkpoint blockade anti-PD-L1 to enhance antitumor efficacy in orthotopic model of PDA. Together, our data is consistent with the notion that tumor associated macrophages lacking CCR1 expression are less immunosuppressive, consequently allowing increased CD8 T cell mediated anti-tumor immunity. Targeting CCR1 in combination with immune checkpoint blockade improves antitumor efficacy in pancreatic cancer.
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Project description:In human patients and in mouse models, immunosuppressive regulatory T cells(Tregs)accumulate in Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesions to pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Here, using a genetically engineered mouse that allows at will depletion of Tregs during pancreatic carcinogenesis, we determined that Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumorprogression. We demonstratedthat Treg depletion resultsin changes in the fibroblast population, exemplified by loss of Smooth Muscle Actinexpression and an increase the myeloid recruiting chemokines Ccl3, Ccl6, and Ccl8. Treg depletion further resulted ina compensatoryinflux of suppressive myeloid cells, thereby preventing an anti-tumor immune response. Mechanistically, we show that themyeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor associated myeloid cells and several ligands up-regulated in epithelial cells and fibroblasts upon Treg depletion. Finally,blockade of CCR1 signalingcombined with Treg-depletionsuccessfully inhibitedtumorigenesis, uncovering the immune-suppressive myeloid CCR1 axis as a potential therapeutic targetin pancreatic cancer.
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Project description:The interactions between chemokines and their receptors, particularly in the context of inflammation, are complex with individual receptors binding multiple ligands and individual ligands interacting with multiple receptors. In addition, there are numerous reports of simultaneous co-expression of multiple inflammatory chemokine receptors on individual inflammatory leukocyte subtypes. Overall, this has previously been interpreted as redundancy and proposed as a protective mechanism to ensure that the inflammatory response is robust. In contrast we have hypothesised that the system is not redundant but exquisitely subtle. Our interests relate to the receptors CCR1, CCR2, CCR3 and CCR5 which, together, regulate non-neutrophilic myeloid cell recruitment to inflammatory sites. Here we demonstrate that, whilst most murine monocytes exclusively express CCR2, there is a small subpopulation, which is expanded during inflammation, which co-expresses CCR1 and CCR2. Combinations of transcript and functional analysis demonstrate that this is not redundant expression and that co-expression of CCR1 and CCR2 marks a phenotypically distinct population of monocytes characterised by expression of genes otherwise typically associated with neutrophils. Single cell RNA sequencing confirms this as a monodisperse population of atypical monocytes. This monocytic population has been previously described as having immunosuppressive activity. Overall, our data confirm combinatorial chemokine receptor expression by a subpopulation of monocytes but demonstrate that this is not redundant expression and marks a discrete monocytic population.
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Project description:The interactions between chemokines and their receptors, particularly in the context of inflammation, are complex with individual receptors binding multiple ligands and individual ligands interacting with multiple receptors. In addition, there are numerous reports of simultaneous co-expression of multiple inflammatory chemokine receptors on individual inflammatory leukocyte subtypes. Overall, this has previously been interpreted as redundancy and proposed as a protective mechanism to ensure that the inflammatory response is robust. In contrast we have hypothesised that the system is not redundant but exquisitely subtle. Our interests relate to the receptors CCR1, CCR2, CCR3 and CCR5 which, together, regulate non-neutrophilic myeloid cell recruitment to inflammatory sites. Here we demonstrate that, whilst most murine monocytes exclusively express CCR2, there is a small subpopulation, which is expanded during inflammation, which co-expresses CCR1 and CCR2. Combinations of transcript and functional analysis demonstrate that this is not redundant expression and that co-expression of CCR1 and CCR2 marks a phenotypically distinct population of monocytes characterised by expression of genes otherwise typically associated with neutrophils. Single cell RNA sequencing confirms this as a monodisperse population of atypical monocytes. This monocytic population has been previously described as having immunosuppressive activity. Overall, our data confirm combinatorial chemokine receptor expression by a subpopulation of monocytes but demonstrate that this is not redundant expression and marks a discrete monocytic population.
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Project description:This study is designed to understand the role of immunosuppressive regulatory B cells (Breg) in pancreatic cancer. Breg and conventional B cells (Bcon) from patients are compared by RNA sequencing analysis.
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