In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis
Wei Liu, … , Lu Li, Zhutian Zeng
Wei Liu, … , Lu Li, Zhutian Zeng
Published February 23, 2023
Citation Information: J Clin Invest. 2023;133(8):e157937. https://doi.org/10.1172/JCI157937.
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In situ expansion and reprogramming of Kupffer cells elicit potent tumoricidal immunity against liver metastasis

Abstract

Liver metastasis represents one of the most frequent malignant diseases with no effective treatment. Functional reprogramming of Kupffer cells (KCs), the largest population of hepatic macrophages, holds promise for treating liver cancer, but remains seldom exploited. Taking advantage of the superior capacity of KCs to capture circulating bacteria, we report that a single administration of attenuated Escherichia coli producing clustered regularly interspersed short palindromic repeats CasΦ (CRISPR/CasΦ) machinery enables efficient editing of genes of interest in KCs. Using intravital microscopy, we observed a failure of tumor control by KCs at the late stage of liver metastasis due to KC loss preferentially in the tumor core and periphery, resulting in inaccessibility of these highly phagocytic macrophages to cancer cells. Simultaneous disruption of MafB and c-Maf expression using the aforementioned engineered bacteria could overcome KC dysfunction and elicit remarkable curative effects against several types of metastatic liver cancer in mice. Mechanistically, bacterial treatment induced massive proliferation and functional reprogramming of KCs. These cells infiltrated into the tumor, dismantled macrometastases by nibbling cancer cells, and skewed toward proinflammatory macrophages to unleash antitumor T cell responses. These findings provide an immunotherapy strategy that could be applicable for treating liver metastasis and highlight the therapeutic potential of targeting tissue-resident macrophages in cancer.

Authors

Wei Liu, Xia Zhou, Qi Yao, Chen Chen, Qing Zhang, Keshuo Ding, Lu Li, Zhutian Zeng

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Figure 4

Therapeutic effects against liver metastasis by bacteria-mediated disruption of c-Maf/MafB in KCs.

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Therapeutic effects against liver metastasis by bacteria-mediated disrup...
(A) Representative images showing ClearColi captured by KCs at 1 hour after infection in tumor-bearing mice. Scale bars: 200 μm. Original magnification, zoomed images: × 5.6. (B) Mice were treated with E. coli–vector or E. coli–sgMafb/Maf at day 7 after B16F10 tumor inoculation and were harvested at day 15 as illustrated. (C) Liver weight and tumor area on the surface of the liver were quantified. n = 8–9 mice per group pooled from 2 experiments. (D) Treatment of late-stage B16F10 melanoma liver metastasis as depicted. (E) Liver weights at day 19 were measured. (F) Mouse survival was monitored. Pooled data of 22–25 mice per group from 4 independent experiments. (G–I) Treatment of late-stage MC38 liver metastasis. Pooled data of 8–11 mice per group from 2 independent experiments. (J–K) Treatment of late-stage LLC liver metastasis. Pooled data of 8–9 mice per group from 2 independent experiments. Scale bars: 1 cm (B, D, G, and J). For E and H, mice that reached the end point of the experiment were euthanized before harvest and were excluded from liver weight analysis. Arrows in F and I indicate time points of bacterial treatment. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t test (C, E, H and K); 2-sided log-rank test (F and I).