Abstract
Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma trials. Here, we found that ICBs induce cerebral edema in some patients and mice with glioblastoma. Through single-cell RNA sequencing, intravital imaging, and CD8+ T cell blocking studies in mice, we demonstrated that this edema results from an inflammatory response following antiprogrammed death 1 (PD1) antibody treatment that disrupts the blood–tumor barrier. Used in lieu of immunosuppressive corticosteroids, the angiotensin receptor blocker losartan prevented this ICB-induced edema and reprogrammed the tumor microenvironment, curing 20% of mice which increased to 40% in combination with standard of care treatment. Using a bihemispheric tumor model, we identified a “hot” tumor immune signature prior to losartan+anti-PD1 therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients.
Original language | English (US) |
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Article number | e2219199120 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 120 |
Issue number | 6 |
DOIs | |
State | Published - Feb 7 2023 |
Externally published | Yes |
Keywords
- biomarkers
- glioblastoma
- immune checkpoint blockers
- immune-related adverse events
- tumor microenvironment
ASJC Scopus subject areas
- General