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

doi:10.1016/j.ccell.2019.05.005

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.

Authors

Jian Qiao¹, Zhida Liu², Chunbo Dong², Yan Luan³, Anli Zhang², Casey Moore⁴, Kai Fu³, Jianjian Peng³, Yang Wang², Zhenhua Ren², Chuanhui Han², Ting Xu⁵, Yang-Xin Fu⁶

Affiliations

¹ The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
² The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China.
⁴ The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Dingfu Biotarget Co. Ltd., Suzhou, Jiangsu 215125, China. Electronic address: [email protected].
⁶ The Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; The Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].

PMID: 31185213
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