Development of the method for reinforcement of the antitumor immunity for head and neck cancer based on the analyses of immnunometabolism using the mouse model

• Project/Area Number: 20K21648
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
• Research Institution: Kanazawa University
• Principal Investigator: Wakisaka Naohiro 金沢大学, 医学系, 協力研究員 (70377414)
• Project Period (FY): 2020-07-30 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 頭頸部癌 / 免疫代謝 / ミトコンドリア / Toll-like receptor 4 / ミトコンドリア代謝経路 / 免疫プロフィール / TLR4経路 / 動物モデル / モデルマウス / 腫瘍免疫 / リンパ球

Outline of Research at the Start

近年、免疫担当細胞で代謝が促進すると機能が向上することが指摘されている。一方、癌
組織では抗腫瘍免疫の主役であるTリンパ球の解糖系代謝と抗腫瘍活性がともに低下してい
ることが報告されている。本研究ではモデルマウスを作成して頭頸部癌の個々の患者のTリンパ球の代謝を解析し、その結果に基づいてTリンパ球の代謝を促進する薬剤を免疫療法と併用してその抗腫瘍効果を評価する。さらに、癌組織のリンパ流が最初に流入するセンチネルリンパ節のTリンパ球の代謝を促進する薬剤を選択し、リンパ節転移を抑制する効果も評価する。

Outline of Final Research Achievements

This study was performed to elucidate the immunometabolic pathways of the T lymphocytes which were associated with antitumor immunity. Using a formalin fixation pathology specimen, the expressions of mRNAs were analyzed by a digital spatial profiler to elucidate an immunometabolic pathways.The analyses showed that the most significant immunometabolic process was mitochondria-related pathway, but not the glycolytic pathway to regulate the tumor progression. In addition, it was revealed that Toll-like receptor 4-related pathway greatly contributed to their activation.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により頭頸部癌の免疫代謝プロセスのさらなる解明が見込まれ、さらに将来、腫瘍免疫を活性化するための薬剤選択など頭頸部癌免疫療法による患者予後の改善が見込まれる。
加えてミトコンドリア経路が免疫代謝に深く関与し、そしてそこにToll-like receptor 4経路が関与することが示されたことで、学術的にも本研究から派生して咽頭癌症例の扁桃における細菌叢の解明が進み、その結果、さらに新しい治療法の開発が見込まれる意義は大きい。

Research Products

• [Journal Article] Lymph node metastasis regulation by peritumoral tonsillar tissue mitochondria-related pathway activation in oropharyngeal cancer (2024)
  • Author(s): Wakisaka Naohiro、Moriyama-Kita Makiko、Kondo Satoru、Kobayashi Eiji、Ueno Takayoshi、Nakanishi Yosuke、Endo Kazuhira、Sugimoto Hisashi、Yoshizaki Tomokazu
  • Journal Title: PLOS ONE Volume: 19 Issue: 2 Pages: e0299750-e0299750
  • DOI: 10.1371/journal.pone.0299750
  • Peer Reviewed / Open Access
• [Journal Article] Immune-Related Gene Expression Profile at Peritumoral Tonsillar Tissue Is Modified by Oropharyngeal Cancer Nodal Status (2023)
  • Author(s): Wakisaka Naohiro、Moriyama-Kita Makiko、Kondo Satoru、Kobayashi Eiji、Ueno Takayoshi、Nakanishi Yosuke、Endo Kazuhira、Sugimoto Hisashi、Yoshizaki Tomokazu
  • Journal Title: The American Journal of Pathology Volume: 193 Issue: 8 Pages: 1006-1012
  • DOI: 10.1016/j.ajpath.2023.04.010
  • Peer Reviewed / Open Access
• [Journal Article] Macroscopic and multiple metastases in sentinel lymph node biopsy are respectively associated with poor prognosis in early oral cancer (2023)
  • Author(s): Kondo Takahito、Tsukahara Kiyoaki、Kawakita Daisuke、Yoshimoto Seiichi、Miura Kouki、Sugasawa Masashi、Chikamatsu Kazuaki、Matsuzuka Takashi、Oze Isao、Kitamura Morimasa、Murakami Yoshiko、Otozai Shinji、Shinozaki Takeshi、Ohba Shinichi、Araki Koji、Mizumachi Takatsugu、et al
  • Journal Title: International Journal of Clinical Oncology Volume: 28 Issue: 4 Pages: 512-520
  • DOI: 10.1007/s10147-023-02305-1
  • Peer Reviewed / Open Access
• [Journal Article] Repression of DERL3 via DNA methylation by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma (2022)
  • Author(s): Kondo S, Okabe A, Nakagawa T, Matsusaka K, Fukuyo M, Rahmutulla B, Dochi H, Mizokami H, Kitagawa Y, Kurokawa T, Mima M, Endo K, Sugimoto H, Wakisaka N, Misawa K, Yoshizaki T, Kaneda A.
  • Journal Title: Biochimica et Biophysica Acta - Molecular Basis of Disease Volume: 1869(2) Issue: 2 Pages: 166598-166598
  • DOI: 10.1016/j.bbadis.2022.166598
  • Peer Reviewed / Open Access
• [Journal Article] Protein Farnesylation on Nasopharyngeal Carcinoma, Molecular Background and Its Potential as a Therapeutic Target (2022)
  • Author(s): Kobayashi Eiji、Kondo Satoru、Dochi Hirotomo、Moriyama-Kita Makiko、Hirai Nobuyuki、Komori Takeshi、Ueno Takayoshi、Nakanishi Yosuke、Hatano Miyako、Endo Kazuhira、Sugimoto Hisashi、Wakisaka Naohiro、Yoshizaki Tomokazu
  • Journal Title: Cancers Volume: 14 Issue: 12 Pages: 2826-2826
  • DOI: 10.3390/cancers14122826
  • Peer Reviewed / Open Access
• [Journal Article] Estrogen induces the expression of <scp>EBV</scp> lytic protein <scp>ZEBRA</scp> , a?marker of poor prognosis in nasopharyngeal carcinoma (2022)
  • Author(s): Dochi H、Kondo S、Murata T、Fukuyo M、Nanbo A、Wakae K、Jiang P、Hamabe T、Tanaka M、Nishiuchi T、Mizokami H、Moriyama M、Kobayashi E、Hirai N、Komori T、Ueno T、Nakanishi Y、Hatano M、Endo K、Sugimoto H、Wakisaka N、Juang H、Muramatsu M、Kaneda A、Yoshizaki T
  • Journal Title: Cancer Science Volume: 113 Issue: 8 Pages: 2862-2877
  • DOI: 10.1111/cas.15440
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EBV genome variations enhance clinicopathological features of nasopharyngeal carcinoma in a non‐endemic region (2022)
  • Author(s): Kondo Satoru、Okuno Yusuke、Murata Takayuki、Dochi Hirotomo、Wakisaka Naohiro、Mizokami Harue、Moriyama‐Kita Makiko、Kobayashi Eiji、Kano Makoto、Ueno Takayoshi、et al.
  • Journal Title: Cancer Science Volume: 113 Issue: 7 Pages: 2446-2456
  • DOI: 10.1111/cas.15381
  • Peer Reviewed / Open Access
• [Journal Article] Intra-arterial chemotherapy targeting metastatic cervical lymph nodes in head and neck cancer (2021)
  • Author(s): Murono S, Komori T, Endo K, Kondo S, Wakisaka N, Yoshizaki T.
  • Journal Title: Acta Otolaryngol Volume: 141 Issue: 12 Pages: 1063-1069
  • DOI: 10.1080/00016489.2021.2003858
  • Peer Reviewed / Open Access
• [Journal Article] In Response to Low Skeletal Muscle Mass Is a Risk Factor for Aspiration Pneumonia (2021)
  • Author(s): Endo Kazuhira、Ueno Takayoshi、Hirai Nobuyuki、Komori Takeshi、Nakanishi Yosuke、Kondo Satoru、Wakisaka Naohiro、Yoshizaki Tomokazu
  • Journal Title: The Laryngoscope Volume: 132 Issue: 2
  • DOI: 10.1002/lary.29792
  • Peer Reviewed
• [Journal Article] Epstein?Barr Virus LMP1 Induces Soluble PD-L1 in Nasopharyngeal Carcinoma (2021)
  • Author(s): Kase Kina、Kondo Satoru、Wakisaka Naohiro、Dochi Hirotomo、Mizokami Harue、Kobayashi Eiji、Kano Makoto、Komori Takeshi、Hirai Nobuyuki、Ueno Takayoshi、Nakanishi Yosuke、Hatano Miyako、Endo Kazuhira、Moriyama-Kita Makiko、Sugimoto Hisashi、Yoshizaki Tomokazu
  • Journal Title: Microorganisms Volume: 9 Issue: 3 Pages: 603-603
  • DOI: 10.3390/microorganisms9030603
  • Peer Reviewed / Open Access
• [Journal Article] Xenografts derived from patients with head and neck cancer recapitulate patient tumour properties (2021)
  • Author(s): Makita Haruna、Endo Kazuhira、Kasahara Yoshiya、Nakata Asuka、Moriyama?kita Makiko?、Ishikawa Kazuya、Ueno Takayoshi、Nakanishi Yosuke、Kondo Satoru、Wakisaka Naohiro、Gotoh Noriko、Yoshizaki Tomokazu
  • Journal Title: Oncology Letters Volume: 21 Issue: 5 Pages: 385-385
  • DOI: 10.3892/ol.2021.12646
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 上咽頭癌におけるEBV-LMP1によるDNAメチル化誘導機構の網羅的解析 (2022)
  • Author(s): 近藤悟, 溝上晴恵, 土地宏朋, 上野貴雄, 中西庸介, 遠藤一平, 脇坂尚宏, 吉崎智一
  • Organizer: 日本耳鼻咽喉科頭頸部外科学会
• [Presentation] 遺伝子発現プロフィールの解析による中咽頭癌の転移有無予測法の開発 (2021)
  • Author(s): 脇坂尚宏・吉崎智一
  • Organizer: 第23回 SNNS研究会