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An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I
Young Rock Chung, … , Slim Fourati, Pablo Penaloza-MacMaster
Young Rock Chung, … , Slim Fourati, Pablo Penaloza-MacMaster
Published June 11, 2024
Citation Information: J Clin Invest. 2024;134(15):e178945. https://doi.org/10.1172/JCI178945.
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Research Article Immunology

An attenuated lymphocytic choriomeningitis virus vector enhances tumor control in mice partly via IFN-I

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Abstract

Viral vectors are being used for the treatment of cancer. Yet, their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple tumor models that injection of tumor-bearing mice with this vector results in improved tumor control and survival. Importantly, r3LCMV improved tumor control in immunodeficient Rag1–/– mice and MyD88–/– mice, suggesting that multiple pathways contributed to the antitumoral effects. The antitumoral effects of r3LCMV were also observed when this vector was administered several weeks before tumor challenges, suggesting the induction of trained immunity. Single-cell RNA sequencing analyses, antibody blockade experiments, and knockout models revealed a critical role for host-intrinsic IFN-I in the antitumoral efficacy of r3LCMV vectors. Collectively, these data demonstrate potent antitumoral effects by r3LCMV vectors and unveil multiple mechanisms underlying their antitumoral efficacy.

Authors

Young Rock Chung, Bakare Awakoaiye, Tanushree Dangi, Nahid Irani, Slim Fourati, Pablo Penaloza-MacMaster

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Figure 5

scRNA-Seq reveals enrichment of IFN-I responses by r3LCMV therapy.

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scRNA-Seq reveals enrichment of IFN-I responses by r3LCMV therapy.
We pe...
We performed gene expression analyses to understand the effects of r3LCMV on different cell subsets within the tumor microenvironment at day 4 after treatment. (A) Uniform manifold approximation and projection (UMAP) plots showing cell distribution based on RNA expression. Each cell is colored by its inferred subset (based on the Immunological Genome Project [ImmGen] database). Cells harboring LCMV reads are indicated by a black dot. (B) Level of expression of LCMV L and S transcripts on different cell subsets from r3LCMV-treated mice. (C) Volcano plot showing the differential expression of genes in tumor cells harboring LCMV reads versus those without LCMV reads. The dashed line indicates P value adjusted for multiple testing of 0.05. ISGs are indicated in red. (D) Enrichment for ISGs in different cell subsets. (E) ISGs on tumor cells harboring LCMV or not harboring LCMV. This panel shows that tumor cells with LCMV reads express higher levels of ISGs relative to tumor cells without LCMV reads. For each box plot, the vertical line indicates the median, the box indicates the interquartile range, and the whiskers indicate 1.5 times the interquartile range. Approximately 80% of cells were CD45+ (after MACS purification). Each group represents pooled tumors from 5 different mice. Indicated P values were calculated by Wilcoxon’s test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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