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

Cancer Cell. 2019 Jun 10;35(6):901-915.e4. doi: 10.1016/j.ccell.2019.05.005.

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.

Keywords: IL-10; TILs; apoptosis; immunotherapy; toxicity; tumor targeting.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / pharmacokinetics
  • Antineoplastic Agents, Immunological / pharmacology*
  • Apoptosis / drug effects*
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Communication
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cetuximab / pharmacokinetics
  • Cetuximab / pharmacology*
  • Coculture Techniques
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Interleukin-10 / pharmacokinetics
  • Interleukin-10 / pharmacology*
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Recombinant Fusion Proteins / pharmacology
  • Signal Transduction
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • Recombinant Fusion Proteins
  • Interleukin-10
  • Cetuximab