A VEGFC-expressing mRNA construct improved immunotherapy response in mouse models of glioblastoma.
Major Finding: A VEGFC-expressing mRNA construct improved immunotherapy response in mouse models of glioblastoma.
Mechanism: Increased VEGFC levels promoted lymphatic drainage and increased tumor-specific T-cell populations.
Impact: These findings may translate into a means to improve immunotherapy response in glioblastoma.
The central nervous system (CNS) is considered an immune-privileged site, partially owing to a lack of lymphatic drainage—and this may contribute to the poor immune response typically elicited by brain tumors such as glioblastomas. Song and colleagues found that mice orthotopically injected with glioblastoma cells did not develop tumors when VEGFC, a lymphangiogenesis-promoting protein, was prophylactically introduced via injection of an adeno-associated viral vector into the cerebrospinal fluid. This protective effect of VEGFC was dependent on drainage to the deep cervical lymph nodes, which are the predominant draining lymph nodes of the CNS, and required CD4+ and CD8+ T cells. Analysis of data from The Cancer Genome Atlas and the Genotype-Tissue Expression project revealed that human glioblastomas exhibited low expression of VEGFC. Further, inspection of the results of a recently published dataset derived from patients with glioblastoma treated with anti–PD-1 revealed that high VEGFC expression was associated with increased markers of T-cell infiltration. Notably, although anti–PD-1 therapy has been demonstrated to be of little benefit in patients with glioblastoma, mice with established glioblastomas treated with anti–PD-1 and an mRNA construct designed to express VEGFC exhibited increased responses to the immunotherapy and had more tumor-specific T cells in the deep cervical lymph nodes. Additionally, in mice injected intracranially with melanoma cells, treatment with the VEGFC mRNA construct improved survival following immune-checkpoint blockade to an extent similar to that achieved by peripheral priming with melanoma cells injected into the flank. Together, these results support the the notion that ectopic VEGFC expression can enhance lymphatic drainage from the CNS in mice, increasing CNS immune surveillance such that immunotherapy may eradicate CNS tumors, providing a rationale for investigation of this phenomenon in humans.
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