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Characterizing the tumor microenvironment of metastatic ovarian cancer by single cell transcriptomics

ABSTRACT: Characterizing the tumor microenvironment of metastatic ovarian cancer by single cell transcriptomics

PROVIDER: PRJNA612966 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11319261_1.fastq.gz	Fastqsanger.gz
	SRR11319261_2.fastq.gz	Fastqsanger.gz
	SRR11319262_1.fastq.gz	Fastqsanger.gz
	SRR11319262_2.fastq.gz	Fastqsanger.gz
	SRR11319263_1.fastq.gz	Fastqsanger.gz

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Characterizing the tumor microenvironment of metastatic ovarian cancer by single cell transcriptomics

Project description:Understanding the cellular composition of the tumor microenvironment and the interactions of the cells is essential to the development of successful immunotherapies in cancer. We perform single-cell RNA sequencing (scRNA-seq) of 9,885 cells isolated from the omentum in 6 patients with ovarian cancer and identify 9 major cell types, including cancer, stromal, and immune cells. Transcriptional analysis of immune cells stratifies our patient samples into 2 groups: (1) high T cell infiltration (high Tinf) and (2) low T cell infiltration (low Tinf). TOX-expressing resident memory CD8+ T (CD8+ Trm) and granulysin-expressing CD4+ T cell clusters are enriched in the high Tinf group. Concurrently, we find unique plasmablast and plasma B cell clusters, and finally, NR1H2+IRF8+ and CD274+ macrophage clusters, suggesting an anti-tumor response in the high Tinf group. Our scRNA-seq study of metastatic tumor samples provides important insights in elucidating the immune response within ovarian tumors.

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Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-? regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-? signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-? into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-? works as a tumor progressor through PD-L1 induction. The source of IFN-? in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-? and expression microarray analysis was performed, and probes showing significantly higher values in IFN-?-added group were termed “IFN-? signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-? signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-? in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-?-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment. Genome-wide transcriptional changes in human ovarian cancer tissue were observed in different tumor immunological microenvironment.

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Project description:High-grade serous (HGS) ovarian cancer is the most common and aggressive ovarian cancer type, and the most lethal gynaecological disease 1,2. The major cause is its highly metastatic nature and the limited availability of effective therapies to oppose it. The omentum is a highly vascularised visceral depot of adipose tissue with immune functions, which becomes the preferential metastatic site in patients with HGS ovarian cancer 1,2. The omentum provides an environment that supports the rapid growth of metastatic tumours and their spread within the peritoneal cavity and adjacent organs 2,3. Research aimed at understanding the biology of metastatic tumours in the omentum is therefore essential to find strategies to oppose HGS ovarian cancer. To this aim, there is the need for in vitro models that faithfully recapitulate the microenvironment of HGS omental metastasis in patients.

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