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

Livia Gozzellino¹Alice Costa²Margherita Nannini^1,3Maria Concetta Nigro¹Carmine Pizzi^1,4Francesco Angeli^1,4Luca Bergamaschi^1,4Chiara Baldovini⁵Barbara Corti⁵Luisa Di Sciascio⁵Davide Pacini^1,6Gianluca Folesani⁶Mauro Gargiulo^1,7Luigi Lovato⁸Ilenia Motta¹Gianandrea Pasquinelli^1,9Annalisa Astolfi^1,2*Maria Abbondanza Pantaleo^1,3

• ¹Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
• ²IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ³Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁴Cardiovascular Division, Morgagni-Pierantoni University Hospital, Forlì, Italy
• ⁵Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁶Cardiac Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁷Vascular Surgery Unit, IRCCS, University Hospital Policlinico S.Orsola, Bologna, Italy
• ⁸Pediatric and Adult CardioThoracic and Vascular, Oncohematologic and Emergency Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ⁹Division of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

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. 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. 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+ 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. 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.