Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis

Jian Qiao, Zhida Liu, Chunbo Dong, Yan Luan, Anli Zhang, Casey Moore, Kai Fu, Jianjian Peng, Yang Wang, Zhenhua Ren, Chuanhui Han, Ting Xu, Yang Xin Fu

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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. Qiao et al. generate a Cetuximab-based IL-10 fusion protein for EGFR-targeted delivery of IL-10 to tumors, in which IL-10 regulates IFN-γ production by dendritic cells and enhances CD8+ T cell-dependent antitumor responses. The fusion protein shows high efficacy alone and in combination with anti-PD-L1/CTLA-4.

Original languageEnglish (US)
Pages (from-to)901-915.e4
JournalCancer Cell
Volume35
Issue number6
DOIs
StatePublished - Jun 10 2019

Keywords

  • IL-10
  • TILs
  • apoptosis
  • immunotherapy
  • toxicity
  • tumor targeting

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Qiao, J., Liu, Z., Dong, C., Luan, Y., Zhang, A., Moore, C., Fu, K., Peng, J., Wang, Y., Ren, Z., Han, C., Xu, T., & Fu, Y. X. (2019). Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis. Cancer Cell, 35(6), 901-915.e4. https://doi.org/10.1016/j.ccell.2019.05.005