Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy.
(1) Kondo T (2) Morita R (3) Okuzono Y (4) Nakatsukasa H (5) Sekiya T (6) Chikuma S (7) Shichita T (8) Kanamori M (9) Kubo M (10) Koga K (11) Miyazaki T (12) Kassai Y (13) Yoshimura A
Using a coculture of stromal cells expressing the notch ligand, Kondo et al. converted activated CD4+ and CD8+ T cells into a memory-like state, characterized by lack of surface PD-1 and CTLA-4, increased expression of Bcl 2, strong anti-tumor activity, and a high proliferative and survival potential in vivo, possibly due to reduced expression of the cell cycle regulator p53.
(1) Kondo T (2) Morita R (3) Okuzono Y (4) Nakatsukasa H (5) Sekiya T (6) Chikuma S (7) Shichita T (8) Kanamori M (9) Kubo M (10) Koga K (11) Miyazaki T (12) Kassai Y (13) Yoshimura A
Using a coculture of stromal cells expressing the notch ligand, Kondo et al. converted activated CD4+ and CD8+ T cells into a memory-like state, characterized by lack of surface PD-1 and CTLA-4, increased expression of Bcl 2, strong anti-tumor activity, and a high proliferative and survival potential in vivo, possibly due to reduced expression of the cell cycle regulator p53.
Adoptive T-cell immunotherapy is a promising approach to cancer therapy. Stem cell memory T (TSCM) cells have been proposed as a class of long-lived and highly proliferative memory T cells. CD8+ TSCM cells can be generated in vitro from naive CD8+ T cells via Wnt signalling; however, methods do not yet exist for inducing TSCM cells from activated or memory T cells. Here, we show a strategy for generating TSCM-like cells in vitro (iTSCM cells) from activated CD4+ and CD8+ T cells in mice and humans by coculturing with stromal cells that express a Notch ligand. iTSCM cells lose PD-1 and CTLA-4 expression, and produce a large number of tumour-specific effector cells after restimulation. This method could therefore be used to generate antigen-specific effector T cells for adoptive immunotherapy.
Author Info:
(1) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (2) Department of Microbiology and Immunolog
y, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (3) Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa-shi, Kanagawa 251-8555, Japan. (4) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (5) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (6) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (7) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (8) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. (9) Division of Molecular Pathology, Research Institute for Biomedical Science, Tokyo University of Science, 2641 Yamazaki, Noda-shi, Chiba 278-8510, Japan. Laboratory for Cytokine Regulation, RIKEN Center for Integrative Medical Sciences (IMS), RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan. (10) Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa-shi, Kanagawa 251-8555, Japan. (11) Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa-shi, Kanagawa 251-8555, Japan. (12) Inflammation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chome, Fujisawa-shi, Kanagawa 251-8555, Japan. (13) Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Citation: Nat Commun 2017 May 22 8:15338 Epub05/22/2017
