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Skeletal undifferentiated pleomorphic sarcoma (SUPS) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognosis. It is prone to recur and metastasize. The tumor microenvironment (TME) and the pathophysiology of SUPS are barely described. Single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the landscape of human diseases at an unprecedented resolution, particularly in diseases lacking animal models, such as SUPS. We performed scRNA-seq to analyze tumor tissues and paracancer tissues from a SUPS patient. We identified the cell types and the corresponding marker genes in this SUPS case. We further showed that CD8+ exhausted T cells and Tregs highly expressed PDCD1, CTLA4 and TIGIT. Thus, PDCD1, CTLA4 and TIGIT were identified as potential targets in this case. We applied copy number karyotyping of aneuploid tumors (CopyKAT) to distinguish malignant cells from normal cells in fibroblasts. Our study identified eight malignant fibroblast subsets in SUPS with distinct gene expression profiles. C1-malignant Fibroblast and C6-malignant Fibroblast in the TME play crucial roles in tumor growth, angiogenesis, metastasis and immune response. Hence, targeting malignant fibroblasts could represent a potential strategy for this SUPS therapy. Intervention via tirelizumab enabled disease control, and immune checkpoint inhibitors (ICIs) of PD-1 may be considered as the first-line option in patients with SUPS. Taken together, scRNA-seq analyses provided a powerful basis for this SUPS treatment, improved our understanding of complex human diseases, and may afforded an alternative approach for personalized medicine in the future.

Malignant fibrous histiocytoma (MFH) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognoses, and is prone to recurrence and metastasis. The pathophysiology remains elusive and its therapeutic options are limited. The 5-year recurrence rate of patients is 36–61%. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the pathophysiology of human diseases at unprecedented resolution, particularly in the diseases lacking animal models, such as MFH. We performed scRNA-seq on tumor tissues and adjacent muscle tissues from a patient with MFH. We identified Cell types and the corresponding marker genes by single-cell RNA sequencing. Malignant cells of fibroblasts were evaluated by CopyKAT analysis and differentially expressed genes of sequencing. We identified PDCD1, CTLA4 and TIGIT as potential targets. We further showed that C2_Exhausted CD4 + Treg and C1_Exhausted CD8 + T cell highly expressed PDCD1, CTLA4 and TIGIT. Intervention via PD-1 immune checkpoint inhibitor (tirelizumab) enabled disease control and reduced tumor immunosuppression. Thus, scRNA-seq analyses guide a successful therapeutic intervention in the MFH patient, improve our understanding of complex human diseases and provide an alternative approach to personalized medicine.

Background: Malignant fibrous histiocytoma (MFH) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognoses, and is prone to recurrence and metastasis. The pathophysiology remains elusive and its therapeutic options are limited. The 5-year recurrence rate of patients is 36% to 61%. Progress in single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the pathophysiology of human diseases at unprecedented resolution, particularly in the diseases lacking animal models, such as MFH.Methods: We performed scRNA-seq on tumor tissues and adjacent muscle tissues from a patient with MFH. We identified Cell types and the corresponding marker genes by single-cell RNA sequencing. Malignant cells of fibroblasts were evaluated by CopyKAT analysis and differentially expressed genes of sequencing.Results: We identified PDCD1, CTLA4 and TIGIT as potential targets. We further showed that C2_Exhausted CD4+ Treg and C1_Exhausted CD8+ T cell highly expressed PDCD1, CTLA4 and TIGIT. Intervention via PD-1 immune checkpoint inhibitor (tirelizumab) enabled disease control and reduced tumor immunosuppression. Conclusion: Thus, scRNA-seq analyses guide a successful therapeutic intervention in the MFH patient, improve our understanding of complex human diseases and provide an alternative approach to personalized medicine.