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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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 8

Prior treatment with r3LCMV renders mice more resistant to tumor challenges.

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Prior treatment with r3LCMV renders mice more resistant to tumor challen...
We tested whether mice that had previously been injected with r3LCMV were protected upon subsequent tumor challenges. (A) Experiment outline to evaluate the effect of prior r3LCMV treatment on subsequent tumor challenges (trained immunity). (B) Cytokine responses at day 1 after r3LCMV treatment. (C) Tumor control. (D) The experiment in A was repeated, but mice were treated with IFNAR1-blocking antibodies at the time of tumor challenge (see Methods) to examine the role of IFN-I signaling. (E) Tumor control in the context of IFNAR1 blockade. (F) Survival in the context of IFNAR1 blockade. Cytokine data from B are from 1 experiment with n = 5 mice (naive mice are shown as controls); the experiment was repeated with similar results. Data from C are from 2 experiments, n = 13 per group. Data from D–F are from 2 experiments (n = 4–5 per group). Error bars represent SEM. Indicated P values in cytokine plots were calculated by Welch’s t test. 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.