Cancer Cell
Volume 35, Issue 6, 10 June 2019, Pages 901-915.e4
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Article
Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis

https://doi.org/10.1016/j.ccell.2019.05.005Get rights and content
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Highlights

  • CmAb-(IL10)2 prolongs the half-life of IL-10 and minimizes its toxicity

  • Tumor-targeted IL-10 induces superior antitumor effects over nontargeted IL-10

  • CmAb-(IL10)2 prevents tumor-specific CD8+ TILs apoptosis through IL-10R on DCs

  • CmAb-(IL10)2 overcomes resistance to immune checkpoint blockade

Summary

Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.

Keywords

IL-10
TILs
apoptosis
immunotherapy
tumor targeting
toxicity

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These authors contributed equally

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