학술논문
Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.
Document Type
Article
Author
Datta, Meenal; Chatterjee, Sampurna; Perez, Elizabeth M.; Gritsch, Simon; Roberge, Sylvie; Duquette, Mark; Chen, Ivy X.; Naxerova, Kamila; Kumar, Ashwin S.; Ghosh, Mitrajit; Emblem, Kyrre E.; Mei R. Ng; Ho, William W.; Kumar, Pragya; Krishnan, Shanmugarajan; Xinyue Dong; Speranza, Maria C.; Neagu, Martha R.; Iorgulescu, J. Bryan; Huang, Raymond Y.
Source
Subject
*IMMUNE checkpoint proteins
*CLINICAL trials
*GLIOBLASTOMA multiforme
*LOSARTAN
*ANGIOTENSIN-receptor blockers
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Language
ISSN
0027-8424
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-PDl therapy that predicted long-term survival. Our findings provide the rationale and associated biomarkers to test losartan with ICBs in glioblastoma patients. [ABSTRACT FROM AUTHOR]