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

Abstract

In recent years, immunotherapy for advanced melanoma has been gaining increased attention. The efficacy of anti-cytotoxic T-lymphocyte antigen 4 antibodies, anti-programmed cell death 1 antibodies, and the BRAF V600E kinase inhibitor has been proven in metastatic melanoma. At the same time, adoptive cell transfer has significant effects against metastatic melanoma; however, it is difficult to apply on a broad scale because of the problems related to cell preparation. To overcome these problems, we developed immune cell therapy using induced pluripotent stem (iPS) cells. The benefit of our method is that a large number of cells can be readily obtained. We focused on macrophages for immune cell therapy because macrophage infiltration is frequently observed in solid cancers. In this study, the efficacy of human iPS cell-derived myeloid cell lines (iPS-ML) genetically modified to express type I IFNs against human melanoma cells was examined. The morphology, phagocytic ability, and surface markers of iPS-ML were similar to those of macrophages. The iPS-ML that express type I IFNs (iPS-ML-IFN) showed significant effects in inhibiting the growth of disseminated human melanoma cells in SCID mice. The infiltration of iPS-ML into the tumor nests was confirmed immunohistologically. The iPS-ML-IFNs increased the expression of CD169, a marker of M1 macrophages that can activate antitumor immunity. The iPS-ML-IFNs could infiltrate into tumor tissue and exert anticancer effects in the local tumor tissue. In conclusion, this method will provide a new therapeutic modality for metastatic melanoma.

Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma

“…We previously showed that type I IFN introduced iPS-ML increased the expression of CD169, a marker of M1 macrophages, that can activate antitumor immunity. We also confirmed the infiltration of iPS-ML expressing type I IFN into the tumor nests [7]. Taken together, we believe that immune cell therapy with both iPS-ML-41BBL and iPS-ML expressing type I IFN can overcome the immune-resistant tumor microenvironments, such as types II, III, and IV.…”

“…The benefits of using iPS-ML are its infinite proliferative capacity and ease of genetic modification. We have previously used iPS-ML as effector cells and reported the effectiveness of type I interferon-expressing iPS-ML against some cancers [6,7]. Type I interferon delivery by iPS-ML elicits antitumor immunity via XCR1 + dendritic cells [8].…”

“…After 5 days, the mice were randomly divided into control (n = 8), OVA peptide-pulsed iPS-ML (n = 8), and OVA peptide-pulsed iPS-ML-41BBL (n = groups. The mice in the OVA peptide-pulsed iPS-ML or OVA peptide-pulsed iPS-ML-41BBL groups were injected with 1×107 cells/mouse/injection on days 5-10 and 12-17. (B) Luminescence images showing tumor growth.…”

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

“…iPSDM-based cell therapeutics have been studied mainly in cancer 42, 43 and airway diseases 44 using murine models particularly relating to the protective benefits of macrophage-mediated phagocytosis. The intraperitoneal injection of iPSC-derived myeloid cells 10 genetically engineered to express interferon-β significantly inhibited the growth of human gastric and pancreatic cancers implanted in the peritoneal cavity, 42 as well as inhibiting the growth of disseminated human melanoma cells in immunocompromised SCID mice.…”

“…The intraperitoneal injection of iPSC-derived myeloid cells 10 genetically engineered to express interferon-β significantly inhibited the growth of human gastric and pancreatic cancers implanted in the peritoneal cavity, 42 as well as inhibiting the growth of disseminated human melanoma cells in immunocompromised SCID mice. 43 iPSC-derived primitive macrophages intranasally transferred to the lung matured into alveolar macrophages and eliminated the surfactant protein accumulated as a result of Csf2ra deficiency in mice. 44 Indeed, evidence is emerging that iPSC-derived myeloid cells may have specific advantages as in cell therapeutics.…”