Open AccessCancer therapy with major histocompatibility complex‐deficient and interferon β‐producing myeloid cells derived from allogeneic embryonic stem cells
Author(s) -
Umemoto Satoshi,
Haruta Miwa,
Sakisaka Masataka,
Ikeda Tokunori,
Tsukamoto Hirotake,
Komohara Yoshihiro,
Takeya Motohiro,
Nishimura Yasuharu,
Senju Satoru
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14144
Subject(s) - immunology , embryonic stem cell , myeloid , cancer research , interferon , biology , immune system , stem cell , cancer cell , cancer , induced pluripotent stem cell , major histocompatibility complex , microbiology and biotechnology , genetics , gene , biochemistry
We previously established a method to generate myeloid cells with a proliferative capability from pluripotent stem cells and designated them iPS ‐ ML . Human iPS ‐ ML cells share features with physiological macrophages including the capability to infiltrate into cancer tissues. We observed therapeutic effects of human iPS ‐ ML cells expressing interferon β ( iPS ‐ ML / interferon (IFN) ‐β) in xenograft cancer models. However, assessment of host immune system‐mediated therapeutic and adverse effects of this therapy is impossible by xenograft models. We currently evaluated the therapeutic effects of a mouse equivalent of human iPS ‐ ML / IFN , a mouse embryonic stem (ES) cell‐derived myeloid cell line producing IFN ( ES ‐ ML / IFN ). The ES ‐ ML s producing IFN ‐β (β‐ ML ) and IFN ‐γ (γ‐ ML ) and originating from E14 ES cells derived from the 129 mouse strain (H‐2 b ) were generated, and the MHC ( H‐2K b , D b , and I‐A b ) genes of the ES ‐ ML / IFN were disrupted using the clustered regularly interspaced short palindromic repeats (CRISPR) / CAS 9 method. We used the ES ‐ ML / IFN to treat allogeneic BALB /c mice (H‐2 d ) transplanted with Colon26 cancer cells. Treatment with β‐ ML but not with γ‐ ML cells repressed the growth of colon cancer in the peritoneal cavity and liver. The transferred ES ‐ ML / IFN infiltrated into cancer tissues and enhanced infiltration of T cells into cancer tissues. ES ‐ ML / IFN therapy increased the number of immune cells in the lymphoid organs. Sensitization of both cancer antigen‐specific CD 8 + T cells and natural killer (NK) cells were enhanced by the therapy, and CD 8 + T cells were essential for the therapeutic effect, implying that donor MHC ‐deficient β‐ ML exhibited a therapeutic effect through the activation of host immune cells derived from allogeneic recipient mice. The results suggested the usefulness of HLA ‐deficient human iPS ‐ ML / IFN ‐β cells for therapy of HLA ‐mismatched allogeneic cancer patients.