Interleukin-34 Limits the Therapeutic Effects of Immune Checkpoint Blockade
Naoki Hama,
Takuto Kobayashi,
Nanumi Han,
Fumihito Kitagawa,
Nabeel Kajihara,
Ryo Otsuka,
Haruka Wada,
Hee-kyung Lee,
Hwanseok Rhee,
Yoshinori Hasegawa,
Hideo Yagita,
Muhammad Baghdadi,
Ken-ichiro Seino
Affiliations
Naoki Hama
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Takuto Kobayashi
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Nanumi Han
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Fumihito Kitagawa
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Nabeel Kajihara
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Ryo Otsuka
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Haruka Wada
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Hee-kyung Lee
DNA Link, Inc., Biomedical Science Building 117, Seoul National University College of Medicine, 103 Daehakro, Jongro-gu, Seoul 03080, South Korea
Hwanseok Rhee
DNA Link, Inc., Biomedical Science Building 117, Seoul National University College of Medicine, 103 Daehakro, Jongro-gu, Seoul 03080, South Korea
Yoshinori Hasegawa
Laboratory of Clinical Omics Research, Depertment of Applied Genomics, Kazusa DNA Research Institute, 2-6-7 Kazusa-kamatari, Kisarazu, Chiba 292-0818, Japan
Hideo Yagita
Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
Muhammad Baghdadi
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan
Ken-ichiro Seino
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15 Nishi-7, Sapporo 060-0815, Japan; Corresponding author
Summary: Interleukin-34 (IL-34) is an alternative ligand to colony-stimulating factor-1 (CSF-1) for the CSF-1 receptor that acts as a key regulator of monocyte/macrophage lineage. In this study, we show that tumor-derived IL-34 mediates resistance to immune checkpoint blockade regardless of CSF-1 existence in various murine cancer models. Consistent with its immunosuppressive characteristics, the expression of IL-34 in tumors correlates with decreased frequencies of cellular (such as CD8+ and CD4+ T cells and M1-biased macrophages) and molecular (including various cytokines and chemokines) effectors at the tumor microenvironment. Then, a neutralizing antibody against IL-34 improved the therapeutic effects of the immune checkpoint blockade in combinatorial therapeutic models, including a patient-derived xenograft model. Collectively, we revealed that tumor-derived IL-34 inhibits the efficacy of immune checkpoint blockade and proposed the utility of IL-34 blockade as a new strategy for cancer therapy.
