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Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy: Bulk Tumor RNA Sequencing for Rag2-/- and Rag2+/- primary p53/MCA tumors

ABSTRACT: Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy: Bulk Tumor RNA Sequencing for Rag2-/- and Rag2+/- primary p53/MCA tumors

PROVIDER: PRJNA647722 | ENA |

REPOSITORIES: ENA

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Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy: Bulk Tumor RNA Sequencing for Rag2-/- and Rag2+/- primary p53/MCA tumors

Project description:Abstract: Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

2020-10-21 | GSE154874 | GEO

Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy

Project description:Abstract: Despite impressive responses in some patients, immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Nearly all preclinical immunotherapy studies utilize transplant tumor models, but cure rates of transplant tumors treated with immunotherapy overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors and reveal striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in primary and transplant sarcomas, only transplant tumors are enriched for activated CD8+ T cells associated with tumor clearance. By CIBERSORTx, the immune microenvironment of primary sarcomas in mice transcriptionally resembles most human sarcomas, while transplant sarcomas model the most inflamed sarcomas in patients. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients whose sarcomas have an immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy.

2020-10-21 | GSE148856 | GEO

Transcriptome characterization of radiation-induced sarcomas

Project description:We performed RNA sequencing on secondary sarcomas, arising from previous radiation therapies. We investigated whether such radiation-induced tumours harbour specific genomic and/or transcriptomic alterations compared to sporadic (primary) sarcomas.

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Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy

Project description:Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy

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Transcriptomic profile of a novel hormone receptor positive mammary adenocarcinoma Mca-P1362

Project description:In this study, we conducted a detailed cellular and molecular characterization of MCa-P1362, a novel syngeneic Balb/c mouse model of metastatic breast cancer. MCa-P1362 cancer cells expressed estrogen receptors (ER), progesterone receptors (PR), and HER-2 receptors.

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DNMT3B maintains mCA landscape and regulates mCG status of bivalent promoters in human embryonic stem cells

Project description:In mammalian cells, DNMT3B is known as a de novo DNA methyltransferase. However, its preferential target sites for DNA methylation are largely unknown. By studying CA methylation (mCA) and various histone mark distributions in human embryonic stem cells (hESC), we set up a connection between mCA, H3K36me3, and DNMT3B. We found that mCA, H3K36me3 and DNMT3B signals in hESC are distributed in a 3-level pattern: low level at promoter region, intermediate level before first splicing junction and high level afterward. Knocking out DNMT3B (KO) in hESC demolished mCA, and this further confirmed that DNMT3B is the main enzyme which maintains mCA. Furthermore, the mCA could not be maintained after we deleted the H3K36me3 binding domain, PWWP domain, in DNMT3B. This observation suggests that DNMT3B maintains mCA through its histone interaction. This is the first study that describes the detailed landscape of mCA and its connection with DNMT3B. In contrast to mCA, we only observed a minor reduction of global mCG level from 83.7% to 79.2% after DNMT3B KO. 5256 de novo hypomethylated regions (dnHMRs) were found in the KO cell, in which 57.8% overlapped annotated promoter sites. Intriguingly, most of these promoter dnHMRs were bivalent, possessing both H3K4me3 and H3K27me3. We call them spurious bivalent promoters. Gene ontology (GO) analysis associated spurious bivalent promoters with development and cell differentiation. Overall, we found the importance of DNMT3B for shaping mCA landscape and maintaining the fidelity of bivalent promoter landscape in hESC.

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Single cell analysis reveals distinct immune landscapes in transplant and primary sarcomas that determine response or resistance to immunotherapy.

Project description: Not available

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2012-06-01 | GSE36982 | GEO

Comparison of gene expression profile in RAG2+ B lineage cells from the small intestinal lamina propria and RAG2+ B lineage cells from the bone marrow

Project description:We used a RAG2-GFP reporter mouse to show that RAG+ B lineage cells can be found in the small intestinal lamina proria in normally-housed mice at weaning age. We used microarry expression analysis to compare the RAG2+ population in the gut to the RAG2+ B lineage population in the bone marrow. Microarray was used to compare RAG2+ lamina propria B cells to RAG2+ bone marrow B cells.

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