@article{99fa2688ebc342d5b34e1862c8d8e08a,
title = "Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis",
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.",
keywords = "IL-10, TILs, apoptosis, immunotherapy, toxicity, tumor targeting",
author = "Jian Qiao and Zhida Liu and Chunbo Dong and Yan Luan and Anli Zhang and Casey Moore and Kai Fu and Jianjian Peng and Yang Wang and Zhenhua Ren and Chuanhui Han and Ting Xu and Fu, {Yang Xin}",
note = "Funding Information: We thank the UT Southwestern Flow Cytometry Facility, Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. We thank Dr. Jinming Gao and Dr. Qiang Feng's help of getting the in vivo imaging data. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. This work was in part supported by Cancer Prevention Research Institute of Texas (United States) grants RR150072 and RP180725 to Y.-X.F. Funding Information: We thank the UT Southwestern Flow Cytometry Facility, Institutional Animal Care and Use Committee Animal Resources Center, and Animal Research Center. We thank Dr. Jinming Gao and Dr. Qiang Feng's help of getting the in vivo imaging data. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. This work was in part supported by Cancer Prevention Research Institute of Texas (United States) grants RR150072 and RP180725 to Y.-X.F. Z.L. C.D. and J.Q. performed the experiments and analyzed the data. J.Q. Z.L. C.D. and Y.-X.F. designed experiments and wrote the manuscript. Y.L. K.F. and J.P. characterized CmAb-(IL10)2 stability and purity under T.X.'s supervision. C.M. and C.H. participated in performing some experiments. C.M. contributed to manuscript preparation. A.Z. Y.W. and Z.R. provided some mice and reagents. J.Q. and Y.-X.F. supervised the study. Yan Luan, Kai Fu, Jianjian Peng, and Ting Xu are employees of Dingfu Biotarget and the antibody-IL-10 patent is in the process of application by Dingfu Biotarget. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = jun,
day = "10",
doi = "10.1016/j.ccell.2019.05.005",
language = "English (US)",
volume = "35",
pages = "901--915.e4",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}