CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy
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ORIGINAL ARTICLE
CD1d expression in glioblastoma is a promising target for NKT cell‑based cancer immunotherapy Ayaka Hara1,2 · Ryo Koyama‑Nasu3 · Mariko Takami1 · Takahide Toyoda1 · Takahiro Aoki1 · Fumie Ihara1 · Masayoshi Kobayashi2 · Seiichiro Hirono2 · Tomoo Matsutani2 · Toshinori Nakayama3 · Yasuo Iwadate2 · Shinichiro Motohashi1 Received: 9 May 2020 / Accepted: 12 October 2020 © The Author(s) 2020
Abstract Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cellmediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients. Keywords Glioblastoma · NKT cells · CD1d · Stem-like cell · Retinoic acid · Cancer immunotherapy Abbreviations α-GalCer α-Galactosylceramide E:T Effector-to-target IFNγ Interferon-γ iNKT Invariant natural killer T LDH Lactate dehydrogenase MFI Median fluorescence intensity NOG NOD/Shi-scid IL-2RγKO PBMCs Peripheral blood mononuclear cells Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02742-1) contains supplementary material, which is available to authorized users. * Shinichiro Motohashi [email protected]‑u.jp 1
Department of Medical Immunology, Graduate School of Medicine, Chiba University, 1‑8‑1 Inohana, Chuo‑ku, Chiba 260‑8670, Japan
2
Department of Neurological Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
3
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
RA Retinoic acid RANO Response assessment in neuro-oncology SEM Standard error of the mean TCR T cell receptor TILs Tumor-infiltrating lymphocytes TNFα Tumor necrosis factor-α
Introduction Glioblastoma is the most common form of a malignant primary brain tumor in adults. Despite recent advances in multimodal therapies that combine maximal surgical resection with postoperative adjuvant chemoradiotherapy, median survival is only around 15–16 month
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