IDDF2024-ABS-0238 Single-cell transcriptomic landscape indicates the potential role of immunotherapy in pancreatic angiosarcoma

<h3>Background</h3> Pancreatic angiosarcoma is a rare and highly aggressive tumor originated from lymphatic or vascular endothelial cells with a poor prognosis and few effective treatments. By analyzing the transcriptomic landscape of pancreatic angiosarcoma liver metastasis based on single-cell RNA sequencing, we explored the mechanisms leading to its susceptibility to invasion and metastasis, and tapped into the potential immunotherapeutic targets for the treatment of pancreatic angiosarcoma. <h3>Methods</h3> One patient diagnosed with pancreatic angiosarcoma with liver metastasis was included in this study. Fresh liver metastasis and adjacent normal liver tissues were processed and single-cell sequenced to obtain single-cell transcriptomic data (IDDF2024-ABS-0238 Figure 1 (A)). We characterized the tumor ecosystem of pancreatic angiosarcoma liver metastasis and compared differences in gene expression and enrichment pathways in cellular subpopulations between tumor region and adjacent normal tissues. The expression level of target genes in mainstream targeted therapy and interactions between individual cell populations were also inspected. <h3>Results</h3> Pancreatic angiosarcoma cells did not show significantly upregulated expression of targeted therapeutic genes other than CDK4 and EGFR. Up-regulation of proliferation-related pathways including NF-κB, p53, HIF-1 and MYC signaling pathways and cytoskeletal remodeling-related pathways may contribute to the proliferation and metastasis of tumor cells. Several immune checkpoint genes were significantly upregulated in T/NK cells, including CTLA4, LAG3, PDCD1 and CD38, while myeloid cells highly expressed the immune checkpoints CD40, CD86 and LAG3 (IDDF2024-ABS-0238 Figure 1(B)). We found the existence of a markedly immunosuppressive microenvironment in pancreatic angiosarcoma liver metastasis, as evidenced by a significantly lower intensity of cellular interactions between immune cells in the tumor region than in the adjacent normal tissues (IDDF2024-ABS-0238 Figure 1 (C)). The T/NK cell exhaustion and Treg gene set scores were significantly higher in tumor tissues than in adjacent normal tissues, as were the macrophage angiogenesis score and DC cell immunosuppression score (IDDF2024-ABS-0238 Figure 1 (D)). <h3>Conclusions</h3> In this study, we outlined the presence of an immunosuppressive tumor ecosystem in pancreatic angiosarcoma liver metastasis, suggesting that pancreatic angiosarcoma may be insensitive to most targeted therapies, whereas immunotherapies targeting CD38, LAG3, and PD-L1 (e.g., isatuximab and Opdualag) may be therapeutically effective and worthy of subsequent exploration.