The role of immune editing in malignant melanoma and its therapeutic targeting

• Project/Area Number: 18K08276
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Saitama Medical University
• Principal Investigator: Murakami Takashi 埼玉医科大学, 医学部, 教授 (00326852)
• Co-Investigator(Kenkyū-buntansha): 堀内 大 埼玉医科大学, 医学部, 講師 (30608906)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: メラノーマ / 腫瘍免疫 / 細胞死 / 細菌 / アジュバント / アジュバント性 / 悪性黒色腫 / 腫瘍免疫学 / 腫瘍内微小環境 / モデルマウス / 転移

Outline of Final Research Achievements

While tumor antigens are present in malignant melanoma, the process of its development confers a characteristic immune escape potential. In this study, we sought a way to maximize the anti-tumor immune response that should work to eliminate the tumor. An anaerobic bacterium Salmonella was used to elicit preferable alterations on the melanoma cells. We further found that the bacteria infected B16 melanoma cells and elicited strong host immune responses that had not previously been obtained. Consequently, this study suggests that there is an intrinsic mechanism that confers strong immunogenicity even to melanoma cells with immune escape potential.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果から、メラノーマ進展に伴う免疫逃避能を抑制する方法として細胞内寄生細菌がもたらす細胞変性が強い免疫原になることが示唆された。がん細胞に免疫原性を強力に付与する仕組みが解明されれば、メラノーマ進展に伴う免疫逃避能を抑制する方法の開発が期待できる。がん免疫逃避抑制療法を併用することによって、従来までの標準的ながん薬物治療の効果を最大限に引き出し、がん医療が大きく改善されるにちがいない。

Research Products

• [Journal Article] Anti-Tumor Activity of AZD4547 Against NTRK1 Fusion Positive Cancer Cells Through Inhibition of NTRKs (2021)
  • Author(s): Cho Hanna、Kim Namkyoung、Murakami Takashi、Sim Taebo
  • Journal Title: Frontiers in Oncology Volume: 11 Pages: 757598-757598
  • DOI: 10.3389/fonc.2021.757598
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis of Fluorescent Probes Targeting Tumor-Suppressor Protein FHIT and Identification of Apoptosis-Inducing FHIT Inhibitors (2021)
  • Author(s): Kawaguchi Mitsuyasu、Sekimoto Eriko、Ohta Yuhei、Ieda Naoya、Murakami Takashi、Nakagawa Hidehiko
  • Journal Title: Journal of Medicinal Chemistry Volume: 64 Issue: 13 Pages: 9567-9576
  • DOI: 10.1021/acs.jmedchem.1c00874
  • Peer Reviewed / Open Access
• [Journal Article] Serum exosomal miR‐638 is a prognostic marker of HCC via downregulation of VE‐cadherin and ZO‐1 of endothelial cells (2021)
  • Author(s): Yokota Y, Noda T, Okumura Y, Kobayashi S, Iwagami Y, Yamada D, Tomimaru Y, Akita H, Gotoh K, Takeda Y, Tanemura M, Murakami T, Umeshita K, Doki Y, Eguchi H.
  • Journal Title: Cancer Science Volume: 112 Issue: 3 Pages: 1275-1288
  • DOI: 10.1111/cas.14807
  • Peer Reviewed / Open Access
• [Journal Article] Breaking the cycle: Targeting of NDRG1 to inhibit bi‐directional oncogenic cross‐talk between pancreatic cancer and stroma (2021)
  • Author(s): Geleta B, Park KC, Jansson PJ, Sahni S, Maleki S, Xu Z, Murakami T, Pajic M, Apte MV, Richardson DR, Kovacevic Z.
  • Journal Title: The FASEB Journal Volume: 35 Issue: 2
  • DOI: 10.1096/fj.202002279r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Accuracy of spiked cell counting methods for designing a pre-clinical tumorigenicity study model (2020)
  • Author(s): Osada H, Kawatou M, Takeda M, Jo JI, Murakami T, Tabata Y, Minatoya K, Yamashita JK, Masumoto H.
  • Journal Title: Heliyon Volume: 6 Issue: 7 Pages: 311-318
  • DOI: 10.1016/j.heliyon.2020.e04423
  • Peer Reviewed / Open Access
• [Journal Article] Targeting the HGF/c-MET pathway in advanced pancreatic cancer: a key element of treatment that limits primary tumour growth and eliminates metastasis (2020)
  • Author(s): Xu Z, Pang T, Pothula S, Mekapogu A, Perera C, Murakami T, Goldstein D, Pirola R, Wilson J, Apte M.
  • Journal Title: British Journal of Cancer Volume: 122 Issue: 10 Pages: 1486-1495
  • DOI: 10.1038/s41416-020-0782-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune Checkpoint Inhibition Followed by Tumor Infiltration of Dendritic Cells in Murine Neuro-2a Neuroblastoma (2020)
  • Author(s): Seiichiro Inoue, Yutaka Horiuchi, Yumiko Setoyama, Yuta Takeuchi, Yoshifumi Beck, Takashi Murakami, Akio Odaka
  • Journal Title: J Surg Res. Volume: 253 Pages: 201-213
  • DOI: 10.1016/j.jss.2020.03.059
  • Peer Reviewed / Open Access
• [Journal Article] An Efficient Photodynamic Therapy Treatment for Human Pancreatic Adenocarcinoma. (2020)
  • Author(s): Quilbe A, Morales O, Baydoun M, Kumar A, Mustapha R, Murakami T, Leroux B, de Schutter C, Thecua E, Ziane L, Colombeau L, Frochot C, Mordon S, Delhem N.
  • Journal Title: J Clin Med. Volume: 9(1) Issue: 1 Pages: 192-192
  • DOI: 10.3390/jcm9010192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An In Vivo Mouse Model of Pelvic Recurrence of Human Colorectal Cancer. (2019)
  • Author(s): Yamamoto M, Masubuchi S, Taniguchi K, Tominaga T, Inomata Y, Miyamoto A, Ishizuka T-A, Murakami T, Osumi W, Hamamoto H, Tanaka K, Okuda J, Uchiyama K.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 19630-19630
  • DOI: 10.1038/s41598-019-56152-0
  • Peer Reviewed / Open Access
• [Journal Article] Establishment and characterization of a novel neuroendocrine carcinoma cell line derived from a human ascending colon tumor. (2019)
  • Author(s): Shinji S, Sasaki N, Yamada T, Koizumi M, Matsuda A, Ohta R, Yokoyama Y, Takahashi G, Hotta M, Hara K, Takeda K, Ueda K, Kuriyama S, Ishiwata T, Murakami T, Ueda Y, Kanazawa Y, Yoshida H.
  • Journal Title: Cancer Sci. Volume: 110(12) Issue: 12 Pages: 3708-3717
  • DOI: 10.1111/cas.14221
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of Different Selectivity between Soluble and Membrane-bound Forms of Carcinoembryonic Antigen (CEA) on the Target-mediated Disposition of Anti-CEA Monoclonal Antibodies. (2019)
  • Author(s): Iwano J, Shinmi D, Masuda K, Murakami T, Enokizono J.
  • Journal Title: Drug Metab Dispos. Volume: 47 (11) Issue: 11 Pages: 1240-1246
  • DOI: 10.1124/dmd.119.088179
  • Peer Reviewed / Open Access
• [Journal Article] Al18F-labeled alpha-melanocyte-stimulating hormone (α-MSH) peptide derivative for the early detection of melanoma. (2019)
  • Author(s): Palangka CRAP, Hanaoka H, Yamaguchi A, Murakami T, Tsushima Y.
  • Journal Title: Ann Nucl Med. Volume: 33(10) Issue: 10 Pages: 733-739
  • DOI: 10.1007/s12149-019-01383-4
  • Peer Reviewed / Open Access
• [Journal Article] Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. (2019)
  • Author(s): Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Neoplasia. Volume: 21(7) Issue: 7 Pages: 627-640
  • DOI: 10.1016/j.neo.2019.04.006
  • NAID: 120006948963
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Biodistribution/Biostability Assessment of siRNA after Intravenous and Intratracheal Administration to Mice, Based on Comprehensive Analysis of In Vivo/Ex Vivo/Polyacrylamide Gel Electrophoresis Fluorescence Imaging. (2019)
  • Author(s): Okuda T, Toyoda Y, Murakami T, Okamoto H.
  • Journal Title: Int J Pharm. Volume: 565 Pages: 294-305
  • DOI: 10.1016/j.ijpharm.2019.05.016
• [Journal Article] Low-density lipoprotein receptor expression is involved in the beneficial effect of photodynamic therapy using talaporfin sodium on gastric cancer cells. (2019)
  • Author(s): Kanda T, Sugihara T, Takata T, Mae Y, Kinoshita H, Sakaguchi T, Hasegawa T, Kurumi H, Ikebuchi Y, Murakami T, Isomoto H.
  • Journal Title: Oncol Lett. Volume: 17 Pages: 3261-3266
  • DOI: 10.3892/ol.2019.10004
  • Peer Reviewed / Open Access
• [Journal Article] Third-generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice (2018)
  • Author(s): Nakatake R, Kaibori M, Nakamura Y, Tanaka Y, Matushima H, Okumura T, Murakami T, Ino Y, Todo T, Kon M.
  • Journal Title: Cancer Sci Volume: 109 Issue: 3 Pages: 600
  • DOI: 10.1111/cas.13492
  • Peer Reviewed / Open Access
• [Journal Article] Bioluminescence Image as a Quantitative Imaging Biomarker for Preclinical Evaluation of Cryoablation in a Murine Model. (2018)
  • Author(s): Lamid-Ochir O, Nakajima T, Miyazaki M, Zhang X, Erdene K, Murakami T, Tsushima Y.
  • Journal Title: J Vasc Interv Radiol. Volume: 29 Issue: 7 Pages: 1034-1040
  • DOI: 10.1016/j.jvir.2018.03.013
  • Peer Reviewed / Open Access
• [Journal Article] ScreenFectA およびScreenFectA plusによる遺伝子導入の特徴． (2018)
  • Author(s): 高木 徹、村上 孝
  • Journal Title: 和光純薬時報Technical Report. Volume: 86 Pages: 8-9
• [Presentation] サルモネラ感染がん細胞による抗腫瘍免疫応答の誘導. (2022)
  • Author(s): 堀内 大、岩田亮太郎、安藤優希枝、畑澤さら、中村彰宏、今井 孝、村上 孝.
  • Organizer: 第95回日本細菌学会総会（オンライン開催） 2022年3月29-30日
• [Presentation] Salmonella infected-melanoma cells elicit anti-melanoma T-cell responses. (2021)
  • Author(s): Horiuchi Y, Ando Y, Murakami T.
  • Organizer: 第50回日本免疫学会学術集会 奈良（奈良春日野国際フォーラム） 2021年12月8日-10日
• [Presentation] Activation of antigen-presenting cells by stress-induced senescence-like tumor cells. (2021)
  • Author(s): Ando Y, Horiuchi Y, Murakami T.
  • Organizer: 第50回日本免疫学会学術集会 奈良（奈良春日野国際フォーラム） 2021年12月8日-10日
• [Presentation] Intra-cellular infection of tumor with Salmonella typhimurium primes tumor-antigen specific T-cell responses. (2021)
  • Author(s): Horiuchi Y, Murakami T.
  • Organizer: 第80回日本癌学会学術総会 横浜（パシフィコ横浜） 2021年9月30日-10月3日
• [Presentation] Potential role of senescent-tumor cells toward anti-tumor immunity. (2021)
  • Author(s): Ando Y, Horiuchi Y, Murakami T.
  • Organizer: 第80回日本癌学会学術総会 横浜（パシフィコ横浜） 2021年9月30日-10月3日
• [Presentation] 骨髄由来樹状細胞の神経芽腫細胞貪食に対する免疫チェックポイント阻害による免疫効果の検討. (2021)
  • Author(s): 井上成一朗、堀内 大、竹内優太、村上 孝、小高明雄.
  • Organizer: 第58回日本小児外科学会学術集会. 横浜（パシフィコ横浜） 2021年4月28-30日.
• [Presentation] Combination of anti-PD-1/anti-PD-L1 antibodies promotes tumor cell phagocytosis by bone marrow derived DCs in a murine neuroblastoma model. (2021)
  • Author(s): Inoue S, Horiuchi Y, Setoyama Y, Takeuchi Y, Murakami T, Odaka A.
  • Organizer: 53rd International Society of Pediatric Oncology (SIOP 2021). ON LINE. Oct 21-24, 2021
  • Int'l Joint Research
• [Presentation] Combination of anti-PD-1/anti-PD-L1 antibodies with the distinct character exerts preferable anti-tumor immune cycle in a murine neuroblastoma model. (2020)
  • Author(s): Inoue S, Horiuchi Y, Setoyama Y, Takeuchi Y, Murakami T, Odaka A.
  • Organizer: International Society of Pediatric Oncology (SIOP 2020). Ottawa, Canada. Oct 14-17, 2020.
  • Int'l Joint Research
• [Presentation] Intra-tumoral infection of Salmonella typhimurium primes anti-tumor immune responses against murine B16 melanoma. (2020)
  • Author(s): Horiuchi Y, Murakami T.
  • Organizer: 第79回日本癌学会学術総会. 広島 2020年10月1-3日
• [Presentation] 免疫チェックポイント遮断による腫瘍浸潤リンパ球の抗腫瘍免疫誘導メカニズム解析-exhaustion maker 発現パターンからみたTIL functionの検討- (2020)
  • Author(s): 井上成一朗、堀内 大、竹内優太、瀬戸山由美子、別宮好文、村上 孝、小高明雄.
  • Organizer: 第57回日本小児外科学会学術集会. 東京（都市センターホテル）
• [Presentation] Inhibition of Hepatocyte Growth Factor (HGF) Signalling Pathway in Combination With Chemotherapy Reduces Tumour Burden in an Orthotopic Model of Advanced Pancreatic Cancer. (2019)
  • Author(s): Xu Z, Pang T, Pothula S, Mekapogu A, Perera C, Murakami T, Goldstein D, Pirola R, Wilson J, Apte M.
  • Organizer: The 50th Annual Meeting of American Pancreatic Association. Grand Wailea, Maui, Hawaii, USA, Nov 6-9, 2019.
  • Int'l Joint Research
• [Presentation] Inhibition of Hepatocyte Growth Factor (HGF) Signalling Pathway in Combination With Chemotherapy Reduces Tumour Burden in an Orthotopic Model of Advanced Pancreatic Cancer. (2019)
  • Author(s): Xu Z, Pang T, Pothula S, Mekapogu A, Perera C, Murakami T, Goldstein D, Pirola R, Wilson J, Apte M.
  • Organizer: Australian Gastroenterology Week 2019 (the Gastroenterological Society of Australia) Adelaide Convention Centre, Adelaide, SA, Australia. Sept 8-10, 2019.
  • Int'l Joint Research
• [Presentation] Mobilization of multi-functional tumor infiltrating lymphocytes following co-administration of anti-PD-1/PD-L1 antibodies in a murine neuroblasoma model. (2019)
  • Author(s): Inoue S, Horiuchi Y, Setoyama Y, Takeuchi Y, Beck Y, Murakami T, Odaka A.
  • Organizer: International Society of Pediatric Oncology (SIOP 2019). Lyon, France. Oct 23-26, 2019.
  • Int'l Joint Research
• [Presentation] PD-L1陰性神経芽細胞腫に対する免疫チェックポイント遮断による腫瘍浸潤リンパ球の抗腫瘍免疫誘導メカニズム. (2019)
  • Author(s): 井上成一朗、堀内 大、竹内優太、瀬戸山由美子、別宮好文、村上 孝、小高明雄.
  • Organizer: 第56回日本小児外科学会学術集会. 久留米（久留米シティプラザ）