Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells

Nobuhiro Tsuchiya; Rong Zhang; Tatsuaki Iwama; Norihiro Ueda; Tianyi Liu; Minako Tatsumi; Yutaka Sasaki; Ranmaru Shimoda; Yuki Osako; Yu Sawada; Yosuke Kubo; Azusa Miyashita; Satoshi Fukushima; Zhao Cheng; Ryo Nakaki; Keiyo Takubo; Seiji Okada; Shin Kaneko; Hironobu Ihn; Tsuneyasu Kaisho; Yasuharu Nishimura; Satoru Senju; Itaru Endo; Tetsuya Nakatsura; Yasushi Uemura

doi:10.1016/j.celrep.2019.08.086

Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1⁺ Dendritic Cells

Cell Rep. 2019 Oct 1;29(1):162-175.e9. doi: 10.1016/j.celrep.2019.08.086.

Authors

Nobuhiro Tsuchiya¹, Rong Zhang², Tatsuaki Iwama³, Norihiro Ueda⁴, Tianyi Liu⁵, Minako Tatsumi⁶, Yutaka Sasaki⁷, Ranmaru Shimoda⁸, Yuki Osako⁸, Yu Sawada⁹, Yosuke Kubo¹⁰, Azusa Miyashita¹⁰, Satoshi Fukushima¹⁰, Zhao Cheng¹¹, Ryo Nakaki⁸, Keiyo Takubo¹², Seiji Okada¹³, Shin Kaneko¹⁴, Hironobu Ihn¹⁰, Tsuneyasu Kaisho¹⁵, Yasuharu Nishimura¹⁶, Satoru Senju¹⁷, Itaru Endo⁹, Tetsuya Nakatsura³, Yasushi Uemura¹⁸

Affiliations

¹ Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
² Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
³ Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan.
⁴ Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan; Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
⁵ Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan; Key Laboratory of Cancer Center, Chinese PLA General Hospital, Beijing 100853, China.
⁶ Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
⁷ Department of Stem Cell Biology and Regenerative Medicine, Graduate School of Medical Science, Kansai Medical University, Hirakata 573-1010, Japan.
⁸ Rhelixa, Inc., Tokyo 101-0032, Japan.
⁹ Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan.
¹⁰ Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
¹¹ Department of Hematology, Institute of Molecular Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China.
¹² Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
¹³ Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-8556, Japan.
¹⁴ Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
¹⁵ Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
¹⁶ Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
¹⁷ Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: senjusat@gpo.kumamoto-u.ac.jp.
¹⁸ Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan. Electronic address: yuemura@east.ncc.go.jp.

PMID: 31577946
DOI: 10.1016/j.celrep.2019.08.086

Abstract

Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1⁺ dendritic cells to enhance CD8⁺ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.

Keywords: CXCR3; PD-1; STING; XCR1; cancer immunotherapy; checkpoint blockade; cross-presentation; dendritic cells; induced pluripotent stem cells; type I interferon.

MeSH terms

Animals
Dendritic Cells / immunology*
Immunity / immunology*
Immunotherapy / methods
Induced Pluripotent Stem Cells / immunology*
Interferon Regulatory Factor-3 / immunology
Interferon Type I / immunology*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Myeloid Cells / immunology*
Neoplasms / immunology
Receptors, CXCR3 / immunology
Receptors, Chemokine / immunology*
Tumor Microenvironment / immunology

Substances

Interferon Regulatory Factor-3
Interferon Type I
Receptors, CXCR3
Receptors, Chemokine
XC chemokine receptor 1, mouse