title: Reprogramming of Melanoma Tumor-Infiltrating Lymphocytes to Induced Pluripotent Stem Cells.
abstract: Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients hold great promise for autologous cell therapies. One of the possible applications of iPSCs is to use them as a cell source for producing autologous lymphocytes for cell-based therapy against cancer. Tumor-infiltrating lymphocytes (TILs) that express programmed cell death protein-1 (PD-1) are tumor-reactive T cells, and adoptive cell therapy with autologous TILs has been found to achieve durable complete response in selected patients with metastatic melanoma. Here, we describe the derivation of human iPSCs from melanoma TILs expressing high level of PD-1 by Sendai virus-mediated transduction of the four transcription factors, OCT3/4, SOX2, KLF4, and c-MYC. TIL-derived iPSCs display embryonic stem cell-like morphology, have normal karyotype, express stem cell-specific surface antigens and pluripotency-associated transcription factors, and have the capacity to differentiate in vitro and in vivo. A wide variety of T cell receptor gene rearrangement patterns in TIL-derived iPSCs confirmed the heterogeneity of T cells infiltrating melanomas. The ability to reprogram TILs containing patient-specific tumor-reactive repertoire might allow the generation of patient- and tumor-specific polyclonal T cells for cancer immunotherapy.
authors.affiliation: Department of Surgery, University of Michigan, 1500 E Medical Center Drive, 3410 CC, Ann Arbor, MI 48109-5932, USA.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Saito
authors.affiliation: Center for iPS Cell Research and Application, Kyoto, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; DNAVEC Corporation, Tsukuba, Ibaraki, Japan.
authors.forename: Noemi
authors.initials: N
authors.lastname: Fusaki
authors.affiliation: Department of Surgery, University of Michigan, 1500 E Medical Center Drive, 3410 CC, Ann Arbor, MI 48109-5932, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Sabel
authors.affiliation: Department of Surgery, University of Michigan, 1500 E Medical Center Drive, 3410 CC, Ann Arbor, MI 48109-5932, USA.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
authors.affiliation: Department of Surgery, University of Michigan, 1500 E Medical Center Drive, 3410 CC, Ann Arbor, MI 48109-5932, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109-2200, USA.
authors.forename: Fumito
authors.initials: F
authors.lastname: Ito