Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
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| 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. |
| Year of Publication | 2023
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| Journal | Proceedings of the National Academy of Sciences of the United States of America
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| Volume | 120
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| Issue | 6
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| Pages | e2219199120
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| Date Published | 02/2023
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| ISSN | 1091-6490
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| DOI | 10.1073/pnas.2219199120
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| PubMed ID | 36724255
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