Arg1 expression defines immunosuppressive subsets of immune infiltrating cells in cancer
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ABSTRACT:
PROVIDER: PRJNA449347 | ENA |
REPOSITORIES: ENA
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Project description:Tumor-associated macrophages (TAM) have attracted attention as they can modulate key cancer-related activities, yet TAM represent a heterogenous group of cells that remain incompletely characterized. In growing tumors, TAM are often referred to as M2-like macrophages, which are cells that display immunosuppressive and tumorigenic functions and express the enzyme arginase 1 (Arg1). Here we combined single cell intravital imaging with scRNA seq to uncover the topography and molecular profiles of Arg1+ macrophages in mice. We further assessed how immunotherapeutic interventions impact these cells directly in vivo. We show that: i) Arg1+ macrophages are more abundant in tumors compared to other organs; ii) there exist two morphologically distinct subsets of Arg1 TAM defined by previously unknown markers (Gbp2b, Bst1, Sgk1, Pmepa1, Ms4a7); iii) anti-Programmed Cell Death-1 (aPD-1) therapy decreases the number of Arg1+ TAM while increasing Arg1– TAM; iv) accordingly, pharmacological inhibition of arginase 1 does not synergize with aPD-1 therapy. Overall, this research defines subsets of immunosuppressive myeloid cells with powerful complementary single cell analytical approaches that pave the way for a more intricate understanding of TAM behavior.
2018-12-11 | GSE112865 | GEO
Project description:Coordinated chemokine expression defines macrophage subsets across tissues
| PRJNA936901 | ENA
Project description:Tumor-associated macrophages (TAM) have attracted attention as they can modulate key cancer-related activities, yet TAM represent a heterogenous group of cells that remain incompletely characterized. In growing tumors, TAM are often referred to as M2-like macrophages, which are cells that display immunosuppressive and tumorigenic functions and express the enzyme arginase 1 (Arg1). Methods: Here we combined high resolution intravital imaging with single cell RNA seq to uncover the topography and molecular profiles of immunosuppressive macrophages in mice. We further assessed how immunotherapeutic interventions impact these cells directly in vivo. Results: We show that: i) Arg1+ macrophages are more abundant in tumors compared to other organs; ii) there exist two morphologically distinct subsets of Arg1 TAM defined by previously unknown markers (Gbp2b, Bst1, Sgk1, Pmepa1, Ms4a7); iii) anti-Programmed Cell Death-1 (aPD-1) therapy decreases the number of Arg1+ TAM while increasing Arg1- TAM; iv) accordingly, pharmacological inhibition of arginase 1 does not synergize with aPD-1 therapy. Conclusion: Overall, this research shows how powerful complementary single cell analytical approaches can be used to improve our understanding of drug action in vivo.
| S-EPMC6299430 | biostudies-literature
Project description:Malignant gliomas are common and aggressive primary brain tumors which are incurable by conventional therapies. Immunotherapy with the immune checkpoint inhibitors is not effective due to the highly immunosuppressive tumor microenvironment (TME). Clinical and experimental data show upregulation of Arginase1 (ARG1) expression in rodent and human malignant gliomas. The elevated ARG1 activity leads to depletion of L-arginine required for proliferation of T lymphocytes and natural killer cells. Inhibition of ARG1 in TME may unblock T cell proliferation and activate effective antitumor responses. To explore an antitumor potential of ARG1 inhibition, first we analyzed bulk and single cell RNA sequencing (scRNA-seq) data from human and murine gliomas, and found upregulation of ARG1 expression in malignant gliomas, both in tumor cells and in tumor infiltrating microglia, monocytes/macrophages. We employed the novel, selective arginase inhibitor - OAT-1746 to interfere with microglia-induced glioma invasion in microglia-glioma co-cultures. We determined its antitumor efficacy as a monotherapy and in combination with immunotherapy. In a Matrigel invasion assay OAT-1746 blocked microglia-dependent invasion of U87-MG and LN18 glioma cells better than reference compounds, without affecting cell viability. OAT-1746 effectively crossed the BBB and increased arginine levels in brains of GL261 glioma bearing mice. The compound reduced glioma growth and increased antitumor effects of the anti-PD-1 antibody. Treatment with OAT-1746 modified TME as demonstrated by profound transcriptomic changes visualized by RNA sequencing. Our findings provide the evidence that inhibition of ARG1 in tumor cells and myeloid cells in TME abolishes the immunosuppressive reprograming of myeloid cells and improves the efficacy of immunotherapy.
2021-08-24 | GSE173865 | GEO
Project description:We compared arginase-1+ macrophages (macrophages were defined by flow cytometry as CD45hi CD11b+ Ly6G-) with arginase-1- brain macrophages following traumatic brain injury (TBI) by isolating these cells from YARG transgenic mice, which express YFP under the arginase-1 promoter. Both cell populations were isolated from YARG brain tissues one day following TBI. We also examined the expression profile of peripheral blood monocytes (monocytes were defined by flow cytometry as CD11bhi F4/80+) from injured YARG mice and from normal YARG mice. Peripheral blood samples were compared to TBI brain macrophages to assess gene expression changes before and after infiltration into the brain. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an IRES inserted at the 3' end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21±1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by YFP. Gene expression analysis of Arg1+ and Arg1- brain macrophage populations revealed that these populations were distinct from either classically activated (M1) macrophages or M2 macrophages, with features of both. The Arg1+ cells differed from Arg1- cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI involves recruitment of at least two major macrophage subsets. Overall, our data indicate that the macrophage response to TBI is heterogeneous and unique. Four groups (Arg1- brain macrophages post-TBI, Arg1+ brain macrophages post-TBI, normal blood monocytes, blood monocytes post-TBI) were analyzed. Four replicates of each group were analyzed for a total of 16 samples (only 3 replicates of the blood monocyte groups are included in this submission).
2013-05-01 | E-GEOD-39759 | biostudies-arrayexpress
Project description:Immune cells sense their environment and adapt their state. Deciphering cellular trajectories unfolding over time is fundamental for understanding biology. Empirical in vivo genomic technologies measuring both cell state and time are lacking. Here, we present Zman-seq, a single-cell technology tracking transcriptomic dynamics across time by introducing fluorescent time stamps into immune cells. We applied Zman-seq to resolve immune cell state-transitions of the dysfunctional tumor immune microenvironment (TME) of glioblastoma (GBM). By measuring the exposure time of infiltrating immune cells in the TME, Zman-seq defines the cellular and molecular trajectories underlying immune incompetence in GBM. Within 24 hours, cytotoxic NK cells transitioned to a dysfunctional program regulated by Tgfb1, while monocytes differentiated into immunosuppressive macrophages in 36-48 hours. Anti-TREM2 antagonistic antibody reshaped the TME by redirecting monocytes to pro-inflammatory macrophages. Zman-seq is a broadly applicable technology enabling empirical measurements of differentiation trajectories guiding the development of more efficacious immunotherapies.
2023-12-21 | GSE232040 | GEO
Project description:Coordinated chemokine expression defines macrophage subsets across tissues [scRNA-seq: hSk]
| PRJNA936903 | ENA
Project description:Coordinated chemokine expression defines macrophage subsets across tissues [scRNA-seq: mLu]
| PRJNA936904 | ENA
Project description:Coordinated chemokine expression defines macrophage subsets across tissues [scRNA-seq: mPL]
| PRJNA936907 | ENA
Project description:Coordinated chemokine expression defines macrophage subsets across tissues [scRNA-seq: mTumor]
| PRJNA936908 | ENA