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

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.

SUBMITTER: Datta M

PROVIDER: S-EPMC9963691 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Datta Meenal M Chatterjee Sampurna S Perez Elizabeth M EM Gritsch Simon S Roberge Sylvie S Duquette Mark M Chen Ivy X IX Naxerova Kamila K Kumar Ashwin S AS Ghosh Mitrajit M Emblem Kyrre E KE Ng Mei R MR Ho William W WW Kumar Pragya P Krishnan Shanmugarajan S Dong Xinyue X Speranza Maria C MC Neagu Martha R MR Iorgulescu J Bryan JB Huang Raymond Y RY Youssef Gilbert G Reardon David A DA Sharpe Arlene H AH Freeman Gordon J GJ Suvà Mario L ML Xu Lei L Jain Rakesh K RK

Proceedings of the National Academy of Sciences of the United States of America 20230201 6

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<sup>+</sup> 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 corticosteroid ...[more]

PMID: 36724255

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Project description:BackgroundGlioblastoma (GBM) has been extensively researched over the last few decades, yet despite aggressive multimodal treatment, recurrence is inevitable and second-line treatment options are limited. Here, we demonstrate how high-throughput screening (HTS) in multicellular spheroids can generate physiologically relevant patient chemosensitivity data using patient-derived cells in a rapid and cost-effective manner. Our HTS system identified actinomycin D (ACTD) to be highly cytotoxic over a panel of 12 patient-derived glioma stemlike cell (GSC) lines. ACTD is an antineoplastic antibiotic used in the treatment of childhood cancers. Here, we validate ACTD as a potential repurposed therapeutic for GBM in 3-dimensional GSC cultures and patient-derived xenograft models of recurrent glioblastoma.MethodsTwelve patient-derived GSC lines were screened at 10 µM, as multicellular spheroids, in a 384-well serum-free assay with 133 FDA-approved compounds. GSCs were then treated in vitro with ACTD at established half-maximal inhibitory concentrations (IC50). Downregulation of sex determining region Y-box 2 (Sox2), a stem cell transcription factor, was investigated via western blot and through immunohistological assessment of murine brain tissue.ResultsTreatment with ACTD was shown to significantly reduce tumor growth in 2 recurrent GBM patient-derived models and significantly increased survival. ACTD is also shown to specifically downregulate the expression of Sox2 both in vitro and in vivo.ConclusionThese findings indicate that, as predicted by our HTS, ACTD could deplete the cancer stem cell population within the tumor mass, ultimately leading to a delay in tumor progression.Key points1. High-throughput chemosensitivity data demonstrated the broad efficacy of actinomycin D, which was validated in 3 preclinical models of glioblastoma.2. Actinomycin D downregulated Sox2 in vitro and in vivo, indicating that this agent could target the stem cell population of GBM tumors.

Dataset Information

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

Publications

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

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