Trabectedin decreases myeloid resistance to improve the efficacy of anti-PD1 immunotherapy and delay glioma malignant progression.

Low-grade gliomas (LGGs) are the most common brain tumors diagnosed in adolescents and young adults. LGGs demonstrate a longer latency and are associated with a lower relative risk compared to high-grade gliomas (HGGs), despite their potential to malignantly transform into fatal HGGs. We previously showed that malignant progression of glioma is associated with an accumulation of immunosuppressive myeloid cells that impair anti-tumor T cell function. Trabectedin is an FDA-approved chemotherapy used for the treatment of soft tissue sarcoma that has also been shown to selectively deplete monocytes and macrophages in those cancer types, although its role in modulating the brain tumor microenvironment (TME) has not yet been investigated. Here, we employed a multimodal approach, including mass cytometry, cytokine assay, and bulk RNA sequencing, to investigate the impact of trabectedin on the glioma immune TME in an immunocompetent, transgenic RCAS-tva murine glioma model that recapitulates spontaneous malignant progression. We report that trabectedin significantly decreased bone marrow-derived myeloid cells, alleviated immunosuppressive myeloid phenotypes, and diminished T cell exhaustion while increasing T cell infiltration in the glioma TME. Finally, trabectedin improved the efficacy of immune checkpoint blockade and significantly increased survival in the RCAS-tva glioma progression model.