TY - JOUR
T1 - Immunochemoradiotherapy for patients with oral squamous cell carcinoma
T2 - Augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-rays irradiation
AU - Tano, Tomoyuki
AU - Okamoto, Masato
AU - Kan, Shin
AU - Bando, Takashi
AU - Goda, Hiroyuki
AU - Nakashiro, Koh Ichi
AU - Shimodaira, Shigetaka
AU - Koido, Shigeo
AU - Homma, Sadamu
AU - Fujita, Tomonobu
AU - Sato, Mitsunobu
AU - Yamashita, Naomi
AU - Hamakawa, Hiroyuki
AU - Kawakami, Yutaka
N1 - Funding Information:
Address all correspondence to: Dr Masato Okamoto, Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, 33 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: mokamoto@a2.keio.jp 1This investigation was supported by a grant in aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. All authors agreed to the submission of this article, and there is no conflict of interest to disclose. Received 18 February 2013; Revised 18 February 2013; Accepted 10 April 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13488
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.13488
DO - 10.1593/neo.13488
M3 - Article
C2 - 23814492
AN - SCOPUS:84879620320
SN - 1522-8002
VL - 15
SP - 805
EP - 814
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 7
ER -
