Immunochemoradiotherapy for patients with oral squamous cell carcinoma: Augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-rays irradiation

Tomoyuki Tano, Masato Okamoto, Shin Kan, Takashi Bando, Hiroyuki Goda, Koh Ichi Nakashiro, Shigetaka Shimodaira, Shigeo Koido, Sadamu Homma, Tomonobu Fujita, Mitsunobu Sato, Naomi Yamashita, Hiroyuki Hamakawa, Yutaka Kawakami

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Abstract

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P =.0075 and P =.0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P =.0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Original languageEnglish
Pages (from-to)805-814
Number of pages10
JournalNeoplasia (United States)
Volume15
Issue number7
DOIs
Publication statusPublished - 2013 Jul

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ASJC Scopus subject areas

  • Cancer Research

Cite this

Tano, T., Okamoto, M., Kan, S., Bando, T., Goda, H., Nakashiro, K. I., Shimodaira, S., Koido, S., Homma, S., Fujita, T., Sato, M., Yamashita, N., Hamakawa, H., & Kawakami, Y. (2013). Immunochemoradiotherapy for patients with oral squamous cell carcinoma: Augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-rays irradiation. Neoplasia (United States), 15(7), 805-814. https://doi.org/10.1593/neo.13488