Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells
(1) Tsuchiya N (2) Zhang R (3) Iwama T (4) Ueda N (5) Liu T (6) Tatsumi M (7) Sasaki Y (8) Shimoda R (9) Osako Y (10) Sawada Y (11) Kubo Y (12) Miyashita A (13) Fukushima S (14) Cheng Z (15) Nakaki R (16) Takubo K (17) Okada S (18) Kaneko S (19) Ihn H (20) Kaisho T (21) Nishimura Y (22) Senju S (23) Endo I (24) Nakatsura T (25) Uemura Y
Using mouse SC tumor models, Tsuchiya et al. show that repeated peritumoral injection of IFNα-expressing, induced pluripotent stem cell-derived, proliferating myeloid cells (iPSC-pMCs) controls local and distal tumor growth. This is independent of the STING-IRF-3 pathway and requires IFNα receptor expression by tumor antigen-presenting, cross-priming XCR1+ host DCs, but not host effector or tumor cells. XCR1+ DCs activate and recruit, via CXCR3, perforin- and granzyme- expressing CD8+, but not CD4+ T- or NK- tumor-infiltrating effectors. IFNα-iPSC-pMC antitumor efficacy is enhanced when combined with PD-1/PDL-1 blockade.
Contributed by Paula Hochman
(1) Tsuchiya N (2) Zhang R (3) Iwama T (4) Ueda N (5) Liu T (6) Tatsumi M (7) Sasaki Y (8) Shimoda R (9) Osako Y (10) Sawada Y (11) Kubo Y (12) Miyashita A (13) Fukushima S (14) Cheng Z (15) Nakaki R (16) Takubo K (17) Okada S (18) Kaneko S (19) Ihn H (20) Kaisho T (21) Nishimura Y (22) Senju S (23) Endo I (24) Nakatsura T (25) Uemura Y
Using mouse SC tumor models, Tsuchiya et al. show that repeated peritumoral injection of IFNα-expressing, induced pluripotent stem cell-derived, proliferating myeloid cells (iPSC-pMCs) controls local and distal tumor growth. This is independent of the STING-IRF-3 pathway and requires IFNα receptor expression by tumor antigen-presenting, cross-priming XCR1+ host DCs, but not host effector or tumor cells. XCR1+ DCs activate and recruit, via CXCR3, perforin- and granzyme- expressing CD8+, but not CD4+ T- or NK- tumor-infiltrating effectors. IFNα-iPSC-pMC antitumor efficacy is enhanced when combined with PD-1/PDL-1 blockade.
Contributed by Paula Hochman
Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-alpha-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-alpha-producing iPSC-pMCs (IFN-alpha-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-alpha-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-alpha-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.
Author Info:
(1) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan; Department of Gastroenterological Su
rgery, 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) Rhelixa, Inc., Tokyo 101-0032, Japan. (10) Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan. (11) Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. (12) Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. (13) Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. (14) Department of Hematology, Institute of Molecular Hematology, The Second Xiang-ya Hospital, Central South University, Changsha, Hunan 410011, China. (15) Rhelixa, Inc., Tokyo 101-0032, Japan. (16) Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan. (17) Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860-8556, Japan. (18) Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. (19) Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan. (20) Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama 641-8509, Japan. (21) Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. (22) Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: senjusat@gpo.kumamoto-u.ac.jp. (23) Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan. (24) Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan. (25) 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.
