Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma
Menée à partir d'échantillons tumoraux de patients atteints d'un sarcome synovial et à l'aide notamment d'une technique de séquençage de l'ARN à l'échelle d'une seule cellule, cette étude met en évidence le rôle du gène de fusion SS18–SSX, des macrophages et des lymphocytes T dans le caractère malin des cellules synoviales et démontre une interaction entre échappement immunitaire et processus oncogènes
Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18–SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer–immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18–SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell–mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.
Nature Medicine 2021