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Integrative characterization of oncogenesis and immune response in sarcoma

Abstract : Sarcomas are cancers of mesenchymal origin that comprise more than a hundred different entities. They are mostly rare diseases that occur at all ages, including in children and young adolescents. Due to their rarity and diversity, diagnosis is often missed or delayed. Prognosis is generally poor in cases of advanced or metastatic disease and most treatment approaches rely on unspecific and highly toxic chemotherapy. There is thus an unmet need to improve the diagnosis of sarcomas and develop novel therapeutic approaches for these diseases. RNA sequencing (RNA-seq) is a promising approach for the diagnosis of sarcomas, especially for translocation-related sarcomas that are characterized by chromosome translocations giving rise to fusion genes, such as EWSR1-FLI1 in Ewing sarcoma. Using RNA-seq data of sarcomas of patients profiled at the Institut Curie, I explored the transcriptomic landscape of sarcomas and used machine learning and deep learning techniques to predict sarcoma type based on RNA-seq. This work led to the development of a tool currently in use at the Institut Curie to predict the origin of cancers of unknown primary and improve the diagnosis and prognosis of individual patients in clinical practice.Immunotherapy has revolutionized cancer care for the last decade, however it has had only limited success in sarcomas, supposedly because they are not “immunogenic”. Indeed, most sarcomas, especially translocation-related ones, have a very low tumor mutational burden, which is believed to be the main driving force in the generation of tumor neoantigens recognized by the immune system. To gain further insight into the potential of immune response in sarcoma, I characterized the immune microenvironment and lymphocyte repertoires of multiple types of sarcomas using RNA-seq of tumor samples. While most of them were indeed poorly infiltrated by cells of the immune system, there were some exceptions to this rule suggesting that immunotherapy should be considered in some cases.Another promising finding for immunotherapy of sarcomas was the identification of novel tumor-specific transcripts in multiple types of translocation-related sarcomas. These “neotranscripts” were driven by their characteristic oncogenic chimeric transcription factors such as EWSR1-FLI1 in Ewing sarcoma; some of them were found to be translated by ribosomes into peptides. Therefore, these may represent a source of tumor-specific public neoantigens for immunotherapies of these translocation-related sarcomas.To characterize in detail the immune microenvironment and oncogenic processes of specific sarcomas, single-cell RNA-seq was performed for some of them, notably dedifferentiated liposarcomas (DDLPS). It revealed higher infiltration by immune cells in the dedifferentiated compartment of the tumor, but with more exhausted and immunosuppressive phenotypes. It also allowed to characterize the oncogenic processes of DDLPS and notably the relationship between dedifferentiated and well-differentiated cells inside the same tumor.
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Submitted on : Tuesday, January 25, 2022 - 5:44:56 PM
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Julien Vibert. Integrative characterization of oncogenesis and immune response in sarcoma. Cancer. Université Paris sciences et lettres, 2021. English. ⟨NNT : 2021UPSLS079⟩. ⟨tel-03543120⟩

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