Arg1 expression defines immunosuppressive subsets of immune infiltrating cells in cancer
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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: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:Prostaglandins (PGs) are inflammatory mediators. Aspirin-like non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), an initiating enzyme of PG biosynthesis1. Daily use of aspirin-like drugs lowers the risk of cancer death not only prophylactically but therapeutically suggesting critical roles of PGs in cancer. However, general mechanisms by which PGs contribute to progression of a wide variety of human cancers remain elusive. Here, using scRNAseq analysis comparing immune cells infiltrating human tumors and a syngeneic mouse tumor, we have dissected this issue. We found that in human tumors, COX is dominantly expressed in infiltrating myeloid cells, and, among PG receptors, PGE receptor EP4 and to a less extent EP2 are expressed in both T cells and myeloid cells. DEG analysis between PTGER4hi and PTGER4lo CD8+ T cells indicates downregulation of IL-2-STAT5 signaling, oxidative phosphorylation, glycolysis and Myc targets in EP4hi CD8+ T cells, as revealed by suppressed expression of IL-2 receptor subunit gene and genes of OXPHOS, glycolytic enzymes and ribosomal proteins (RPs). Similar downregulation of OXPHOS, glycolytic enzymes and RP genes is found in PTGER4hi myeloid cells. Notably, such downregulation of OXPHOS and RP genes was found in immune cells infiltrating LLC1 mouse tumor, and reversed by treatment of tumor-bearing mice with EP2 and EP4 antagonists. In vitro in CD8+ T cells, EP4 is induced upon TCR activation and PGE2 acts on EP4, downregulates Il2ra expression and suppresses expression of Myc and PGC-1, thereby impairing both mitochondria and glycolysis as well as ribosome biogenesis in these cells. Similarly, EP4 is induced upon activation in macrophages and PGE2 downregulates Myc and OXPHOS pathwaysin these cells irrespective of other stimuli. These results demonstrate that PGE2 shapes immunosuppressive tumor microenvironment by hampering bioenergetic metabolism and ribosome biogenesis in infiltrating immune cells via EP4 receptor.
2024-09-28 | GSE242272 | GEO
Project description:Prostaglandins (PGs) are inflammatory mediators. Aspirin-like non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX), an initiating enzyme of PG biosynthesis1. Daily use of aspirin-like drugs lowers the risk of cancer death not only prophylactically but therapeutically suggesting critical roles of PGs in cancer. However, general mechanisms by which PGs contribute to progression of a wide variety of human cancers remain elusive. Here, using scRNAseq analysis comparing immune cells infiltrating human tumors and a syngeneic mouse tumor, we have dissected this issue. We found that in human tumors, COX is dominantly expressed in infiltrating myeloid cells, and, among PG receptors, PGE receptor EP4 and to a less extent EP2 are expressed in both T cells and myeloid cells. DEG analysis between PTGER4hi and PTGER4lo CD8+ T cells indicates downregulation of IL-2-STAT5 signaling, oxidative phosphorylation, glycolysis and Myc targets in EP4hi CD8+ T cells, as revealed by suppressed expression of IL-2 receptor subunit gene and genes of OXPHOS, glycolytic enzymes and ribosomal proteins (RPs). Similar downregulation of OXPHOS, glycolytic enzymes and RP genes is found in PTGER4hi myeloid cells. Notably, such downregulation of OXPHOS and RP genes was found in immune cells infiltrating LLC1 mouse tumor, and reversed by treatment of tumor-bearing mice with EP2 and EP4 antagonists. In vitro in CD8+ T cells, EP4 is induced upon TCR activation and PGE2 acts on EP4, downregulates Il2ra expression and suppresses expression of Myc and PGC-1, thereby impairing both mitochondria and glycolysis as well as ribosome biogenesis in these cells. Similarly, EP4 is induced upon activation in macrophages and PGE2 downregulates Myc and OXPHOS pathwaysin these cells irrespective of other stimuli. These results demonstrate that PGE2 shapes immunosuppressive tumor microenvironment by hampering bioenergetic metabolism and ribosome biogenesis in infiltrating immune cells via EP4 receptor.
2024-09-28 | GSE242271 | GEO
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.
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2014-09-23 | E-GEOD-51332 | biostudies-arrayexpress
Project description:A promise of cell replacement therapy using pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) as donor source has been increased. However, particularly when ESCs were used, immune suppression should be required because the donor-recipient combination would be allogeneic. In this study, we examined a concept that some immunosuppressive cells could be induced from PSCs and those cells could prevent allogeneic immune rejection of the PSCs-based transplantation. In fact, we successfully induced immunosuppressive cells that resemble M2 macrophages in terms of cell surface molecule and gene expressions. They efficiently suppressed allogeneic T cell proliferative responses, at least partly, in nitric oxide dependent manner. We applied these cells to in vivoallogeneic transplantation and found that they substantially prolonged ESCs-derived graft survival. These results open a new insight for development of a practical immune-regulatory strategy in cell replacement therapy using PSCs. Difference of the gene expression between ESdSC and ESdDC was analyzed. Two independent experiment were performed.
2014-03-28 | E-GEOD-56302 | biostudies-arrayexpress
Project description:Cancer cells can develop an immunosuppressive tumor microenvironment to control tumor-infiltrating lymphocytes. The underlying mechanisms still remain unclear. Here, we report that mouse and human colon cancer cells acquire lymphocyte membrane proteins including cellular markers such as CD4 and CD45. We observed cell populations harboring both a tumor-specific marker and CD4 in the tumor microenvironment. Sorted cells from these populations were capable of forming organoids, identifying them as cancer cells. Live imaging analysis revealed that lymphocyte membrane proteins were transferred to cancer cells via trogocytosis. As a result of the transfer in vivo, cancer cells also acquired immune regulatory surface proteins such as CTLA4 and Tim3, which suppress activation of immune cells. RNA-sequencing analysis of ex vivo co-cultured splenocytes with trogocytic cancer cells showed reductions in Th1 activation and natural killer cell signaling pathways compared to the non-trogocytic control. Cancer cell trogocytosis was confirmed in the patient-derived xenograft models of colorectal cancer and head and neck cancer. These findings suggest that cancer cells utilize membrane proteins expressed in lymphocytes, which in turn contribute to developing the immunosuppressive tumor microenvironment.
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