Losartan controls immune checkpoint blocker-induced edema and improves survival in glioblastoma mouse models.

Autor:	Datta M; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Chatterjee S; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Perez EM; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; Broad Institute of MIT and Harvard, Cambridge, MA 02142.; Department of Systems Biology, Harvard Medical School, Boston, MA 02115., Gritsch S; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Roberge S; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Duquette M; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Chen IX; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Naxerova K; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Kumar AS; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.; Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142., Ghosh M; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Emblem KE; Department of Physics and Computational Radiology, Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, 0372 Norway., Ng MR; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Ho WW; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142., Kumar P; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Krishnan S; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Dong X; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Speranza MC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Neagu MR; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA., Iorgulescu JB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115., Huang RY; Department of Radiology, Brigham and Women's Hospital, Boston, MA 02115., Youssef G; Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215., Reardon DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Sharpe AH; Broad Institute of MIT and Harvard, Cambridge, MA 02142.; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA., Freeman GJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.; Department of Medicine, Harvard Medical School, Boston, MA 02115., Suvà ML; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.; Broad Institute of MIT and Harvard, Cambridge, MA 02142., Xu L; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Jain RK; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Feb 07; Vol. 120 (6), pp. e2219199120. Date of Electronic Publication: 2023 Feb 01.
DOI:	10.1073/pnas.2219199120
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu