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Viral-Directed Augmentation of Kupffer Cell Cross-Presentation Provokes Antitumor Immunity Against Liver Metastasis
Chen Chen1, Qing Zhang1, Jiajia Li1
1State Key Laboratory of immune response and immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
Abstract:
Liver metastasis is associated with poor prognosis and resistance to immune checkpoint inhibitors. Functional modulation of Kupffer cells (KCs) holds promise as an alternative immunotherapeutic approach. Leveraging their capacity to capture circulating virions, an oncolytic virus-based KC-targeting strategy is developed that demonstrated efficacy and safety in treating multifocal liver metastasis. A single intravenous infusion of the M51R mutant vesicular stomatitis virus (VSV-M51R), but not wild-type (WT) VSV, induced significant tumor regression in mouse models of forced liver metastasis, independent of direct oncolysis. The ineffectiveness of VSV-WT is attributed to its induction of massive KC apoptosis, whereas VSV-M51R replicated transiently within KCs without compromising viability. Instead, VSV-M51R promoted KC proliferation in tumor-adjacent areas, enhancing their access to tumor foci and cross-presentation of tumor antigens. This led to robust activation of hepatic anti-tumor CD8+ T-cell responses, which required mitochondrial antiviral signaling protein-dependent type I interferon triggering in KCs. Depletion of KCs abolished the T cell stimulating and anti-tumor effects of VSV-M51R. Furthermore, simultaneous blockade of programmed cell death-ligand 1(PD-L1) during VSV-M51R treatment achieved remarkable synergistic efficacy in treating monotherapy-resistant late-stage liver metastasis. These findings underscore the pivotal role of KCs in systemic oncolytic virotherapy and offer a potentially applicable strategy for treating advanced liver metastasis.
Insights
A modified vesicular stomatitis virus (VSV-M51R) effectively treats liver metastasis by activating Kupffer cells (KCs) and enhancing anti-tumor T-cell responses. Combining VSV-M51R with PD-L1 blockade shows synergistic efficacy in advanced liver cancer.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Liver metastasis significantly worsens patient prognosis and often resists immune checkpoint inhibitor therapy.
- Kupffer cells (KCs) are key liver-resident macrophages with potential for immunotherapeutic modulation.
- Targeting KCs offers a promising alternative strategy for treating liver metastasis.
Purpose of the Study:
- To develop and evaluate an oncolytic virus-based strategy targeting Kupffer cells for liver metastasis treatment.
- To investigate the mechanism of action of a modified vesicular stomatitis virus (VSV-M51R) in liver metastasis models.
- To assess the synergistic potential of VSV-M51R combined with PD-L1 blockade.
Main Methods:
- Utilized a modified vesicular stomatitis virus (VSV-M51R) and wild-type VSV in mouse models of liver metastasis.
- Administered a single intravenous infusion of the oncolytic virus.
- Assessed tumor regression, KC apoptosis and proliferation, T-cell responses, and combined efficacy with PD-L1 blockade.
Main Results:
- VSV-M51R, but not VSV-WT, induced significant tumor regression independent of direct oncolysis.
- VSV-M51R promoted KC proliferation and enhanced anti-tumor CD8+ T-cell responses via type I interferon signaling.
- KC depletion abrogated the anti-tumor effects of VSV-M51R.
- Combined VSV-M51R and PD-L1 blockade demonstrated synergistic efficacy in resistant, late-stage liver metastasis.
Conclusions:
- VSV-M51R is an effective immunotherapeutic agent for liver metastasis by modulating Kupffer cells and boosting T-cell immunity.
- Kupffer cells play a critical role in the systemic efficacy of oncolytic virotherapy for liver cancer.
- This strategy offers a potential new approach for treating advanced and resistant liver metastasis.
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