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Multi-omics analysis revealed potential use of immunotherapy and CDK4/6 inhibitors in intimal sarcoma
Bei Wang1,2, Rongrong Chen3, Huan Yin3
1Medical Research Center & Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Background:
Intimal sarcoma (IS) and angiosarcoma (AS), two rare yet highly aggressive vascular mesenchymal malignancies, present significant therapeutic challenges due to their scarcity, which underscoring the urgent need to investigate genetic alterations and tumor microenvironment (TME) features for novel therapeutic development.
Methods:
We performed integrated analysis of whole-exome sequencing (WES)/1021-gene panel sequencing, RNA sequencing, and immunohistochemistry (IHC) data from 31 IS and 35 AS patients to identify potential precision therapy.
Results:
Genomic profiling revealed 522 and 518 single nucleotide variants (SNVs) in the IS and AS cohorts, respectively. TP53 mutations predominated in AS versus IS (15/35 vs 2/31, p < 0.001). Conversely, IS exhibited significantly more copy number variants (CNVs), particularly involving the KDR/KIT/PDGFRA locus (chromosome 4) and the CDK4/MDM2 locus (chromosome 12) (p < 0.001). Strikingly, 25/31 (81%) IS patients harbored CDK4 copy number gains or CDKN2A/B losses, compared to only 2/35 (6%) AS patients (p < 0.001). TME analysis revealed no significant inter-group differences overall; however, pulmonary artery IS specimens demonstrated substantial immune infiltration. Notably, reduced CD3+ T-cell density correlated with shorter survival (p =0.029). PD-L1 expression analysis (≥1% cutoff) showed positivity in 6/8 evaluable patients, including 3 with >50% tumor cell staining. Two IS patients receiving postoperative Sintilimab (PD-1 inhibitor) experienced prolonged survival (overall survival: 14+ and 56+ months, respectively).
Conclusions:
This study characterizes the distinct mutation landscape yet similar immune microenvironment of rare IS and AS. Given the frequent cell cycle dysregulation and the observed PD-L1 expression in a subset of patients, CDK4/6 inhibitors and PD-1/PD-L1 inhibitors warrant further clinical investigation for these patients.
Insights
Intimal sarcoma and angiosarcoma show distinct genetic profiles but similar tumor microenvironments. Targeting cell cycle dysregulation and PD-L1 expression may offer new precision therapies for these rare vascular cancers.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Intimal sarcoma (IS) and angiosarcoma (AS) are rare, aggressive vascular cancers with limited treatment options.
- Investigating genetic alterations and tumor microenvironment (TME) is crucial for developing novel therapies.
Purpose of the Study:
- To perform integrated genomic and TME analysis of IS and AS patients.
- To identify potential therapeutic targets for precision medicine in these rare malignancies.
Main Methods:
- Whole-exome sequencing (WES), 1021-gene panel sequencing, RNA sequencing, and immunohistochemistry (IHC) were performed.
- Data from 31 IS and 35 AS patients were analyzed.
Main Results:
- IS and AS exhibit distinct genomic profiles, with IS showing more copy number variants (CNVs) involving cell cycle-related genes (e.g., CDK4, CDKN2A/B).
- TP53 mutations were more frequent in AS.
- TME analysis revealed no significant overall differences, but pulmonary artery IS showed immune infiltration. Reduced CD3+ T-cell density correlated with poorer survival.
- PD-L1 expression was observed in a subset of patients, and PD-1 inhibitor treatment showed promising survival outcomes in two IS patients.
Conclusions:
- IS and AS have unique mutation landscapes but share similarities in their immune microenvironment.
- Frequent cell cycle dysregulation in IS and observed PD-L1 expression suggest potential efficacy of CDK4/6 and PD-1/PD-L1 inhibitors.
- These targeted therapies warrant further clinical investigation for patients with IS and AS.
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