Antitumor immune response of dendritic cells (DCs) expressing tumor-associated antigens derived from induced pluripotent stem cells: In comparison to bone marrow-derived DCs Hiromitsu Iwamoto, Toshiyasu Ojima, Keiji Hayata, Masahiro Katsuda, Motoki Miyazawa, Takeshi Iida, Masaki Nakamura, Mikihito Nakamori, Makoto Iwahashi and Hiroki Yamaue Second Department of Surgery, Wakayama Medical University, School of Medicine, Wakayama 641-8510, Japan It is generally accepted that the difficulty in obtaining a sufficient number of functional dendritic cells (DCs) is a serious problem in DC-based immunotherapy. Therefore, we used the induced pluripotent stem (iPS) cell-derived DCs (iPSDCs). If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. In our study, we induced iPSDCs from iPS cells and examined the capacity for maturation of iPSDCs compared to that of BMDCs in addition to the capacity for migration of iPSDCs to regional lymph nodes. We adenovirally transduced the hgp100 gene, natural tumor antigens, into DCs and immunized mice once with the genetically modified DCs. The cytotoxic activity of CD8 (1) cytotoxic T lymphocytes (CTLs) was assayed using a 51 Cr-release assay. The therapeutic efficacy of the vaccination was examined in a subcutaneous tumor model. Our results showed that iPSDCs have an equal capacity to BMDCs in terms of maturation and migration. Furthermore, hgp100-specific CTLs were generated in mice immunized with genetically modified iPSDCs. These CTLs exhibited as high a level of cytotoxicity against B16 cells as BMDCs. Moreover, vaccination with the genetically modified iPSDCs achieved as high a level of therapeutic efficacy as vaccination with BMDCs. Our study clarified experimentally that genetically modified iPSDCs have an equal capacity to BMDCs in terms of tumor-associated antigen- specific therapeutic antitumor immunity. This vaccination strategy may therefore be useful for future clinical application as a cancer vaccine. Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. 1–3 Many cancer patients worldwide have been treated with cancer vaccine therapy using DCs. Our previous Phase I clinical trial of cancer vaccine therapy using carcino- embryonic antigen peptide-pulsed DCs found the clinical effects of this therapy to be insufficient. 4 Therefore, we next used a gene-based vaccination strategy that used DCs adeno- virally transduced with the entire tumor-associated antigen (TAA) gene. We demonstrated that DCs adenovirally trans- duced with the TAA gene are effective in inducing TAA- specific cytotoxic T lymphocytes (CTLs) and that these cells elicit potent antitumor responses, especially in gastrointestinal solid tumors. 5–8 These findings suggest that this strategy would be useful in clinical application as a cancer vaccine in patients with gastrointestinal tumors, and clinical trials evalu- ating such applications are now under consideration. The issue of limited cells is a serious obstacle for DC vac- cine therapy. DCs created for clinical use are generated from the peripheral blood monocytes of patients. Therefore, a large amount of blood must be collected or leukapheresis must be performed, which is both expensive and time-consuming. An additional problem is that the number of DCs is reduced in the peripheral blood and the function of DCs is impaired in cancer patients. 9,10 Therefore, obtaining a sufficient number of functional DCs remains a serious problem for the applica- tion of DC vaccine therapy. Recent studies have revealed that embryonic stem cell-like pluripotent stem cells, known as induced pluripotent stem (iPS) cells, can be generated from murine and human fibro- blasts. 11,12 Furthermore, it has been reported that DCs can be successfully derived from murine iPS cells (iPSDCs). 13 If the therapeutic efficacy of iPSDCs is equivalent to that of bone marrow-derived DCs (BMDCs), then the aforementioned problems may be solved. Therefore, in our study, we trans- duced the TAA gene into iPSDCs and examined whether the genetically modified iPSDCs can induce TAA-specific CTLs as effectively as BMDCs. In our study, iPSDCs were adenovirally transduced with the entire natural tumor antigen hgp100 gene, 14 and whether vaccination with these genetically engineered iPSDCs can Key words: iPSDCs, DCs vaccine therapy, TAA-specific, genetically modified DCs, antitumor immune response Grant sponsor: Ministry of Education, Culture, Sports, Science and Technology of Japan; Grant number: 23791492 DOI: 10.1002/ijc.28367 History: Received 14 Feb 2013; Accepted 19 June 2013; Online 3 July 2013 Correspondence to: Toshiyasu Ojima, Second Department of Surgery, Wakayama Medical University, School of Medicine, 811-1 Kimiidera, Wakayama 641-8510, Japan, Tel.: 181-73-441-0613, Fax: 181-73-446–6566, E-mail: tojima@wakayama-med.ac.jp Tumor Immunology Int. J. Cancer: 134, 332–341 (2014) V C 2013 UICC International Journal of Cancer IJC