Integrative genomic and immune landscape analysis of intimal sarcomas for emerging therapeutic targets and immunotherapy strategies

Introduction Intimal sarcomas are aggressive mesenchymal tumors arising from the tunica intima of large vessels, mainly the pulmonary artery. They are usually associated with MDM2 amplification. Due to their rarity and scarce sensitivity to chemotherapy, they are characterized by late diagnosis and high mortality. Thus, there is an urgent need to unravel novel therapeutic biomarkers. This study explored the role of the immune infiltrate and molecular profile in an intimal sarcoma cohort to evaluate their amenability to immunotherapy and detect potential targets, apart from MDM2 . Methods Whole transcriptome and whole exome sequencing were performed on 5 intimal sarcoma cases (FFPE) followed by computational analyses, including immune cell profiling, differential gene expression, variant calling and copy number alteration detection. Results All samples presented the amplification of MDM2 , confirming their diagnosis, and the co-amplification of CPM and SLC35E3 . Interestingly, they also showed PD-L1 expression along with a prevalence of CD4+ memory resting T-cells, M2 macrophages and different concentrations of naïve B-cells, CD8+ T-cells and monocytes. The upregulation of immunoglobulins and pathways involved in the immune response (e.g. IL6/JAK/STAT3 and TNF-α via NF-kB signaling, interferon gamma response) further suggested a potential sensitivity to immunotherapy. Discussion Our findings provided basic evidence for immunotherapy efficacy in intimal sarcomas and identified potential molecular targets. Further studies involving larger case series are required to validate these results.