Person:

Mathewson, Nathan

ABSTRACTSynovial sarcoma is an aggressive mesenchymal neoplasm, driven by the SS18-SSX fusion, and characterized by immunogenic antigens expression and exceptionally low T cell infiltration levels. To study the cancer-immune interplay in this disease, we profiled 16,872 cells from 12 human synovial sarcoma tumors using single-cell RNA-sequencing (scRNA-Seq). Synovial sarcoma manifests antitumor immunity, high cellular plasticity and a core oncogenic program, which is predictive of low immune levels and poor clinical outcomes. Using genetic and pharmacological perturbations, we demonstrate that the program is controlled by the SS18-SSX driver and repressed by cytokines secreted by macrophages and T cells in the tumor microenvironment. Network modeling predicted that SS18-SSX promotes the program through HDAC1 and CDK6. Indeed, the combination of HDAC and CDK4/6 inhibitors represses the program, induces immunogenic cell states, and selectively targets synovial sarcoma cells. Our study demonstrates that immune evasion, cellular plasticity, and cell cycle are co-regulated and can be co-targeted in synovial sarcoma and potentially in other malignancies.

Neoantigens, derived from tumor-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses, and can function as bona fide tumor rejection antigens. Here, we demonstrate that a strategy of multi-epitope, personalized neoantigen vaccination, previously tested only in patients with high-risk melanoma, is feasible for tumors such as glioblastoma, which typically have a relatively low mutation load and an immunologically “cold” tumor microenvironment. We immunized patients with newly diagnosed GBM using personalized neoantigen-targeting vaccines following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone, a highly potent corticosteroid frequently prescribed to glioblastoma patients for cerebral edema, generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T-cell responses that were enriched for a memory phenotype, and increased tumor-infiltrating T-cells. Utilizing single-cell T-cell receptor analysis, we provide evidence that neoantigen-specific T-cells from the peripheral blood can migrate into an intracranial glioblastoma tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune milieu of glioblastoma.