Therapy of Peritoneally Disseminated Colon Cancer by TAP-Deficient Embryonic Stem Cell–Derived Macrophages in Allogeneic Recipients

Abstract

We established a method to generate a large quantity of myeloid lineage cells from mouse embryonic stem (ES) cells, termed ES cell–derived proliferating myeloid cell lines (ES-ML). ES-ML continuously proliferated in the presence of M-CSF and GM-CSF. ES-ML genetically modified to express an anti-HER2 (neu) mAb single-chain V region fragment reduced the number of cocultured mouse Colon-26 cancer cells expressing HER2. Stimulation of ES-ML with IFN-γ plus LPS or TNF resulted in almost complete killing of the Colon-26 cells by the ES-ML, and the cytotoxicity was mediated, in part, by NO produced by ES-ML. When ES-ML were injected into mice with i.p. established Colon-26 tumors, they efficiently infiltrated the tumor tissues. Injection of ES-ML with rIFN-γ and LPS inhibited cancer progression in the mouse peritoneal cavity. Coinjection of TNF-transfected or untransfected ES-ML with rIFN-γ inhibited cancer growth and resulted in prolonged survival of the treated mice. In this experiment, transporter associated with Ag processing (TAP)1-deficient ES-ML exhibited therapeutic activity in MHC-mismatched allogeneic recipient mice. Despite the proliferative capacity of ES-ML, malignancy never developed from the transferred ES-ML in the recipient mice. In summary, TAP-deficient ES-ML with anticancer properties exhibited a therapeutic effect in allogeneic recipients, suggesting the possible use of TAP-deficient human-induced pluripotent stem cell–derived proliferating myeloid cell lines in cancer therapy.

Immunotherapy against Metastatic Melanoma with Human iPS Cell–Derived Myeloid Cell Lines Producing Type I Interferons

“…Haga and colleagues reported that allogeneic recipients of TAP-deficient mouse embryonic stem cell-derived ML cells do not develop leukemia (20). In our experiments, even in immune-deficient SCID mice, the injection of iPS-ML cells did not lead to the development of leukemia or other malignancies.…”

Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity

“…We could efficiently immortalize monocytic progenitor cells derived from human iPSCs. Moreover, these iPS-MLs could differentiate into terminally differentiated macrophages (ML-MPs), as previously reported [10,42]. ML-MPs showed enhanced cytokine secretion and therefore were deemed suitable for HTS.…”

Induced Pluripotent Stem Cell Derived Macrophages as a Cellular System to Study Salmonella and Other Pathogens

“…These iPSC-derived Mϕs (iPSDM) are genetically highly related to their original donor cells, share striking phenotypic and functional similarities with primary human Mϕs and are amenable to genetic manipulation. Previous studies utilised iPSDMs to model rare genetic defects that impact Mϕ functions [ 10 – 12 ]; or investigated their utility in cellular therapies [ 13 – 15 ]. However, the potential of iPSDMs in host-pathogen interaction studies, especially to study human adapted pathogens, has not been fully evaluated.…”