The signaling mechanism of immune mediator lactic acid secreted from cancer

• Project/Area Number: 16H04703
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Osaka International Cancer Institute
• Principal Investigator: Inoue Norimitsu 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 総括研究員(腫瘍免疫学部門長) (80252708)
• Co-Investigator(Kenkyū-buntansha): 赤澤 隆 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 主任研究員 (80359299)
• Research Collaborator: Ohashi Toshimitsu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: がん免疫 / がん微小環境 / 乳酸 / 免疫制御 / プロトン / IL-23 / IL-17 / マクロファージ / 癌 / IL23 / IL17

Outline of Final Research Achievements

We have identified that tumor secreted lactic acid, which has been thought to be a terminal metabolite of glycolysis before this, plays an important role in the formation of abnormal immune-microenvironment around cancer. In this study, we showed that both lactic anion and acidic condition independently induce the epigenetic modification. Furthermore, we showed that tumor microenvironment with high level of lactic acid is associated with M2-like macrophage polarization in head and neck cancer. Because the tumor microenvironment with high level of lactic acid directly affects the induction of cancer inflammation and immunoregulation, it is important for us to develop new cancer immunotherapy targeting immune- and metabolic microenvironment.

Academic Significance and Societal Importance of the Research Achievements

がんの免疫療法が実際の臨床に使われ注目を集めている。しかし、現在の方法だけでは、対象が限られており、現法を補完する新しい免疫療法の開発が期待されている。私達は、現法の獲得免疫をターゲットにするのではなく、自然免疫系をターゲットにした新しい治療法の開発を目指している。 特に、がんの代謝と免疫環境との関連を明らかにし、それをターゲットにしたユニークな研究を遂行している。今回、がんによって形成される免疫環境形成のメカニズムの一端を基礎と臨床の両方において解明してきており、今後さらに発展させる必要があると考えられる。

Research Products

• [Journal Article] Safety and effectiveness of eculizumab for adult patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. (2019)
  • Author(s): Kato H, Miyakawa Y, Hidaka Y, Inoue N, Ito S, Kagami S, Kaname S, Matsumoto M, Mizuno M, Matsuda T, Shimono A, Maruyama S, Fujimura Y, Nangaku M, Okada H.
  • Journal Title: Clin Exp Nephrol Volume: 23 Issue: 1 Pages: 65-75
  • DOI: 10.1007/s10157-018-1609-8
  • Peer Reviewed / Open Access
• [Journal Article] Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. (2019)
  • Author(s): Ito S, Hidaka Y, Inoue N, Kaname S, Kato H, Matsumoto M, Miyakawa Y, Mizuno M, Okada H, Shimono A, Matsuda T, Maruyama S, Fujimura Y, Nangaku M, Kagami S.
  • Journal Title: Clin Exp Nephrol Volume: 23 Issue: 1 Pages: 112-121
  • DOI: 10.1007/s10157-018-1610-2
  • Peer Reviewed / Open Access
• [Journal Article] Development of a vaccine based on bacteria-mimicking tumor cells coated with novel engineered TLR2 ligands (2018)
  • Author(s): Akazawa T, Ohashi T, Wijewardana V, Sugiura K, Inoue N.
  • Journal Title: Cancer Science Volume: in press Issue: 5 Pages: 1319-1329
  • DOI: 10.1111/cas.13576
  • Peer Reviewed / Open Access
• [Journal Article] M2-like macrophage polarization in high lactic acid-producing head and neck cancer. (2017)
  • Author(s): Ohashi, T, Aoki, M, Tomita, H, Akazawa, T, Sato, K, Kuze, B, Mizuta, K, Hara, A, Nagaoka, H, Inoue, N, Ito, Y
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 6 Pages: 1128-1134
  • DOI: 10.1111/cas.13244
  • Peer Reviewed / Open Access
• [Journal Article] Development of effective tumor immunotherapy using a novel dendritic cell?targeting Toll-like receptor ligand (2017)
  • Author(s): De Silva Nadeeka H.、Akazawa Takashi、Wijewardana Viskam、Inoue Norimitsu、Oyamada Maremichi、Ohta Atsuko、Tachibana Yuki、Wijesekera Daluthgamage Patsy H.、Kuwamura Mitsuru、Nishizawa Yasuko、Itoh Kazuyuki、Izawa Takeshi、Hatoya Shingo、Hasegawa Tetsuya、Yamate Jyoji、Inaba Toshio、Sugiura Kikuya
  • Journal Title: PLOS ONE Volume: 12 Issue: 11 Pages: 0188738-0188738
  • DOI: 10.1371/journal.pone.0188738
  • Peer Reviewed / Open Access
• [Journal Article] 補体と自然免疫・獲得免疫 (2017)
  • Author(s): 井上徳光
  • Journal Title: 腎と透析 Volume: 83 Pages: 531-537
• [Journal Article] 補体関連検査とその考え方 (2017)
  • Author(s): 大谷克城、井上徳光、若宮伸隆
  • Journal Title: 腎と透析 Volume: 83 Pages: 538-543
• [Journal Article] Three pentraxins C-reactive protein, serum amyloid p component and pentraxin 3 mediate complement activation using Collectin CL-P1 (2017)
  • Author(s): 2.Roy, N., Ohtani, K., Hidaka, Y., Amano, Y., Matsuda, Y., Mori, K., Hwang, I., Inoue, N., Wakamiya, N.
  • Journal Title: Biochim Biophys Acta Volume: 861 Issue: 2 Pages: 1-14
  • DOI: 10.1016/j.bbagen.2016.11.023
  • NAID: 120006715888
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Collectin CL-P1 utilizes C-reactive protein for complement activation. (2016)
  • Author(s): 5.Roy, N., Ohtani, K., Matsuda, Y., Mori, K., Hwang, I., Suzuki, Y., Inoue, N., Wakamiya, N.
  • Journal Title: Biochim Biophys Acta Volume: 1860 Issue: 6 Pages: 1118-1128
  • DOI: 10.1016/j.bbagen.2016.02.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of the T cell receptor beta chain repertoire in tumor infiltrating lymphocytes (2016)
  • Author(s): Nakanishi, K., Kukita, Y., Segawa, H., Inoue, N., Ohue, M., Kato, K.
  • Journal Title: Cancer Medicine Volume: 5 Issue: 9 Pages: 2513-2521
  • DOI: 10.1002/cam4.828
  • Peer Reviewed / Open Access
• [Journal Article] MIWI2 as an effector of DNA methylation and gene silencing in embryonic male germ cells (2016)
  • Author(s): 7.Kojima-Kita, K., Kuramochi-Miyagawa, S., Ogonuki, N., Ogura, A., Hasuwa, H., Akazawa, T., Inoue, N., Nakano, T.
  • Journal Title: Cell Reports Volume: 16 Issue: 11 Pages: 2819-28
  • DOI: 10.1016/j.celrep.2016.08.027
  • Peer Reviewed / Open Access
• [Presentation] がんの高乳酸環境と免疫制御 (2018)
  • Author(s): 井上徳光
  • Organizer: 第22回日本がん免疫学会総会
  • Invited
• [Presentation] 頭頸部癌におけるWaruburg効果と腫瘍内M2様マクロファージの解析 (2018)
  • Author(s): 大橋敏充、青木光広、赤澤隆、柴田博史、久世文也、井上徳光、伊藤八次
  • Organizer: 第22回日本がん免疫学会総会
• [Presentation] FDG-PET/CTを用いた腫瘍内M2様マクロファージの評価 (2018)
  • Author(s): 大橋敏充、柴田博史、赤澤隆、井上徳光
  • Organizer: 第77回日本癌学会学術集会
• [Presentation] 「お笑い」が免疫に及ぼす影響の網羅的な解析ー笑いとがん医療の実証研究ー (2018)
  • Author(s): 赤澤隆、井上徳光、松浦成昭、宮代勲
  • Organizer: 第77回日本癌学会学術集会
• [Presentation] Establishment of a comprehensive complement examination system for complement-related diseases by the Japanese Association for Complement Research (JACR) (2017)
  • Author(s): Hidaka, Y., Inoue, N., Ohtsuka, Y., Sawai, T., Miyata, T., Ohsawa, I., Ohtani, K., Okada, H., Kinoshita, T., Sekine, H., Tsukamoto, H., Nakao, M., Mizuno, M., Murakami, Y., Horiuchi, T., Wakamiya, N.
  • Organizer: 6th International Conference "HUS & related diseases"
  • Int'l Joint Research
• [Presentation] Establishment of a comprehensive complement examination system for complement-related diseases by the Japanese Association for Complement Research (JACR) (2017)
  • Author(s): Hidaka, Y., Inoue, N., Ohtsuka, Y., Sawai, T., Miyata, T., Ohsawa, I., Ohtani, K., Okada, H., Kinoshita, T., Sekine, H., Tsukamoto, H., Nakao, M., Mizuno, M., Murakami, Y., Horiuchi, T., Wakamiya, N.
  • Organizer: 16th European Meeting on Complement in Human Disease
  • Int'l Joint Research
• [Presentation] 高乳酸頭頸部癌における M2 様マクロファージ分化の促進 (2017)
  • Author(s): 大橋 敏充、青木 光広、赤澤 隆、久世 文也、水田 啓介、井上 徳光、 伊藤 八次
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] がん微小環境における乳酸と免疫応答 (2017)
  • Author(s): 井上徳光
  • Organizer: 第15回がんとハイポキシア研究会
  • Invited
• [Presentation] 補体関連疾患とその検査システムの構築 (2017)
  • Author(s): 井上徳光
  • Organizer: 第52回日本小児腎臓病学会学術集会
  • Invited
• [Presentation] 補体のABCとその病気 (2017)
  • Author(s): 井上徳光
  • Organizer: 第33回腎移植・血管外科研究会
  • Invited
• [Presentation] 補体関連疾患に対する網羅的な補体検査システムの構築 (2017)
  • Author(s): 井上徳光
  • Organizer: 第54回日本補体学会学術集会
  • Invited
• [Presentation] 補体を知って補体の病気を考える (2017)
  • Author(s): 井上徳光
  • Organizer: 第59回日本小児血液・がん学会学術集会
  • Invited
• [Presentation] 補体関連疾患に対する網羅的な補体検査システムの構築 (2017)
  • Author(s): 井上 徳光、日高 義彦、大谷 克城、若宮 伸隆
  • Organizer: 第１回日本免疫不全・自己炎症学会学術集会
• [Presentation] 補体とTMA (2017)
  • Author(s): 井上徳光
  • Organizer: 第45回日本集中治療医学会学術集会
  • Invited
• [Presentation] Application of CR4-targeting antitumor immunoadjuvant for an advanced dendritic cell therapy (2016)
  • Author(s): Akazawa,T., Sugiura, K., Inaba,T., Inoue, N.
  • Organizer: XXVI International Complement Workshop
  • Place of Presentation: ホテル日航金沢（石川・金沢）
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] Paroxysmal nocturnal hemoglobinuria caused by PIGT mutations: Atypical PNH (2016)
  • Author(s): Murakami, Y., Inoue, N., Kawamotoi, M., Kohara, N., Kinoshita, T.
  • Organizer: XXVI International Complement Workshop
  • Place of Presentation: ホテル日航金沢（石川・金沢）
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] Collectin CL-P1 is involved in C-reactive protein-mediated complement activation (2016)
  • Author(s): Roy, N., Ohtani, K., Yasuyuki Matsuda, Y., Kenichiro Mori, K., Hwang, I, Suzuki, Y., Inoue, N., Wakamiya, N.
  • Organizer: XXVI International Complement Workshop
  • Place of Presentation: ホテル日航金沢（石川・金沢）
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] Establishment of a comprehensive complement examination system for complement-related diseases by the Japanese Association for Complement Research (2016)
  • Author(s): Hidaka, Y., Inoue, N., Ohtsuka, Y., Sawai, T., Miyata, T., Osawa, I., Okada, H., Kinoshita, T., Sekine, H., Takahashi, M., Tsukamoto, H., Nakao, M., Nonaka, M., Matsushita, M., Yamamoto, T., Horiuchi, T., Wakamiya N.
  • Organizer: XXVI International Complement Workshop
  • Place of Presentation: ホテル日航金沢（石川・金沢）
  • Year and Date: 2016-09-04
  • Int'l Joint Research
• [Presentation] がんが放出する乳酸によるヒストン修飾制御機構 (2016)
  • Author(s): 井上徳光, 赤澤隆
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪国際交流センター（大阪・大阪）
  • Year and Date: 2016-07-27
• [Book] シンプル微生物学（改訂第6版） (2018)
  • Author(s): 井上徳光、赤澤隆、小熊 惠二、堀田 博、若宮 伸隆ら
  • Total Pages: 474
  • Publisher: 南江堂
  • ISBN: 9784524254835
• [Book] Paroxysmal Nocturnal Hemoglobinuria-From bench to bedside (2017)
  • Author(s): Norimitsu Inoue, Taroh Kinoshita, Yuzuru Kanakura, Jun-ichi Nishimura
  • Total Pages: 358
  • Publisher: Springer
• [Book] Paroxysmal Nocturnal Hemoglobinuria-From bench to bedside (2017)
  • Author(s): Inoue, N., Kinoshita, T.
  • Total Pages: 358
  • Publisher: Springer Japan
• [Remarks] 和歌山県立医科大学 分子遺伝学講座
  • URL: http://www.wakayama-med.ac.jp/dept/igakubu/1606031/index.html
• [Remarks] 大阪国際がんセンター研究所腫瘍免疫学
  • URL: http://www.mc.pref.osaka.jp/laboratory/department/shuyou/
• [Remarks] 大阪国際がんセンター研究所腫瘍免疫学部門ホームページ
  • URL: http://www.mc.pref.osaka.jp/laboratory/department/shuyou/