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

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 3

r3LCMV exerts antitumoral effects independent of CD8+ T cells and B7/CD28 costimulation.

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r3LCMV exerts antitumoral effects independent of CD8+ T cells and B7/CD2...
(A–C) Effect of r3LCMV vectors in the B16-B2m–/– melanoma model. (A) Experiment outline for evaluating the role of MHC I. (B) Tumor control. (C) Survival. (D and E) Effect of LCMV vectors on tumor-specific CD8+ T cell responses. (D) Experiment outline for measuring tumor-specific CD8+ T cells in the tumor. (E) Tumor-specific CD8+ T cells at day 8 after treatment. (F and G) Upregulation of B7 costimulatory molecules by r3LCMV. (F) CD80 and CD86 costimulatory molecules on dendritic cells from tumor-draining lymph nodes. Dendritic cells were gated on live, CD3–, NK1.1–, Ly-6G–, CD19–, CD11b+, CD11c+ at day 4 after treatment. (G and H) Effect of B7 costimulation blockade, CD8+ T cell depletion, and CD4+ T cell depletion. B7.1/B7.2-blocking antibodies, CD8+ T cell–depleting antibodies, or CD4+ T cell–depleting antibodies were administered i.p. every 3 days (see Methods for dosing information). (G) Experiment outline for evaluating the role of T cells and costimulation. (H) Tumor control. (I–K) Effect of virus-specific CD8+ T cells. (I) Experiment outline for evaluating the role of virus-specific T cell activation. (J) Representative FACS plots showing P14 cell expansion in PBMCs at day 7 after treatment. (K) Tumor control. Data from A–C are pooled from 2 experiments (one experiment with n = 10 per group and another with n = 10 per group). Data from D and E are pooled from 2 experiments (one experiment with n = 9 per group and another with n = 9–12 per group). Data from F are from 1 representative experiment (n = 4 per group). Data from G and H are from 1 representative experiment (n = 6–7 per group). Data from I–K are from 1 representative experiment (n = 6–7 per group). Error bars represent SEM. Indicated P values in the tumor volume plots were calculated by the Mann-Whitney test, or by Kruskal-Wallis test with Dunn’s multiple-comparison test when comparing more than 2 groups. Indicated P values in the survival plot were calculated by the log rank test.