Effective anti-cancer immunotherapy by controling autophagy

• Project/Area Number: 24501331
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Shimane University
• Principal Investigator: HARADA Mamoru 島根大学, 医学部, 教授 (50260716)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 癌免疫療法 / アポトーシス / TRAIL / オートファジー / 癌

Outline of Final Research Achievements

Autophagy is a cell survival system under starvation or stress. Cancer cells utilize this system to acquire therapy-resistance and adjust hypoxic tumor microenvironment. I found that autophagy is induced when human pancreatic cancer cells are treated with apoptosis-inducing TRAIL. Additionally, their susceptibility to TRAIL is significantly augmented by the treatment with RNA interference or molecular-targeted drugs to inhibit autophagy.

Research Products

• [Journal Article] Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state (2015)
  • Author(s): Tongu M, Harashima N, Tamada K, Chen L, Harada M
  • Journal Title: Cancer Sci. Volume: 106 Pages: 9-17
  • DOI: 10.1111/cas.12568
  • NAID: 120005982740
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prognostic impact of programmed cell death 1 expression in human leukocyte antigen class I-positive hepatocellular carcinoma after curative hepatectomu (2015)
  • Author(s): Umemoto Y, Okano S, Matsumoto Y, Nakagawara H, Matono R, Yoshiya S, Yamashita YI, Yoshizumi T, Ikegami T, Soejima Y, Harada M, Aishima S, Oda Y, Shirabe K, Maehara Y.
  • Journal Title: Journal of Gastroenterolog Volume: not determined Pages: 65-67
  • DOI: 10.1007/s00535-014-0933-3
  • Peer Reviewed / Open Access
• [Journal Article] New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles. (2015)
  • Author(s): Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco M A, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H.
  • Journal Title: Int Immunopharmacol. Volume: 26 Pages: 133-138
  • DOI: 10.1016/j.intimp.2015.03.023
  • Peer Reviewed / Open Access
• [Journal Article] Transfection of poly(I:C) can induce reactive oxygen species-triggered apoptosis and interferon--mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system (2014)
  • Author(s): Harashima N, Minami T, Uemura H, Harada M
  • Journal Title: Mol Cancer. Volume: 13 Pages: 217-217
  • DOI: 10.1186/1476-4598-13-217
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition (2014)
  • Author(s): amaki H, Harashima N, Hiraki M, Arichi N, Nishimura N, Shiina H, Naora K, Harada M
  • Journal Title: Oncotarget Volume: 5 Pages: 11399-11412
  • NAID: 120005982736
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Identification of erythropoietin receptor-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma (2014)
  • Author(s): Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco M, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H.
  • Journal Title: International Immunopharmacology Volume: 20 Pages: 59-65
  • DOI: 10.1016/j.intimp.2014.02.018
  • Peer Reviewed / Open Access
• [Journal Article] Metronomic chemotherapy with low-dose cyclophophamide plus gemcitabine can induce anti-tumor T cell immunity in vivo (2013)
  • Author(s): Miki Tongu, Nanae Harashima, Hiroyuki Monma, Touko Inao, Takaya Yamada, Hideyuki Kawauchi, Mamoru Harada
  • Journal Title: Cancer Immunology Immunotherapy Volume: 62 Pages: 383-391
  • DOI: 10.1007/s00262-012-1343-0
  • Peer Reviewed
• [Journal Article] The HSP70 and autophagy inhibitor pifithrin-μ enhances the antitumor effects of TRAIL on human pancreatic cancer. (2013)
  • Author(s): Monma H, Harashima N, Inao T, Okano S, Tajima Y, and Harada M
  • Journal Title: Mol Cancer Ther. Volume: 12(4) Pages: 341-351
  • DOI: 10.1158/1535-7163.mct-12-0954
  • NAID: 120005982741
  • Peer Reviewed
• [Journal Article] Pifithrin-mu, an inhibitor of heat-shock protein 70, can increase the antitumor effects of hyperthermia against human prostate cancer cells (2013)
  • Author(s): Sekihara M, Harashima N, Tongu M, Tamaki Y, Uchida N, Inomata T, Harada M.
  • Journal Title: PLoS One Volume: 8
  • DOI: 10.1371/journal.pone.0078772
  • Peer Reviewed
• [Journal Article] Interleukin-17A is involved in enhan-cement of tumor progression in murine intestine (2012)
  • Author(s): K.Oshiro
  • Journal Title: Immunobiology Volume: 217 Pages: 54-60
  • DOI: 10.1016/j.imbio.2011.08.002
  • Peer Reviewed
• [Journal Article] Oral ingestion of Lentinula edodes mycelia extract can restore the antitumor T cell response of mice inoculated with colon-26 cells into the subserosal space of the cecum. (2012)
  • Author(s): Harada M, et al.(5人中5番目)
  • Journal Title: Oncology Reports Volume: 27 Pages: 325-332
  • DOI: 10.3892/or.2011.1549
  • Peer Reviewed
• [Journal Article] Role of the PI3K/Akt pathway and autophagy in TLR3 signaling-induced apoptosis and growth arrest of humna prostate cancer cells. (2012)
  • Author(s): Harashima N, Inao T, Imamura R, Okano S, Suda T, Harada M.
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 61 Pages: 667-676
  • Peer Reviewed
• [Journal Article] Antitumor effects of cytoplasmic delivery of an innate adjuvant receptor ligand, poly(I:C), on human breast cancer. (2012)
  • Author(s): Harada M., et al.(8人中8番目)
  • Journal Title: Breast Cancer Res Treat. Volume: (in press) Pages: 89-100
  • DOI: 10.1007/s10549-011-1930-3
  • Peer Reviewed
• [Journal Article] Combining a peptide vaccine with oral ingestion of lentinula edodes mycelia extract enhances anti-tumor activity in B16 melanoma-bearing mice. (2012)
  • Author(s): Tanaka K, Harashima N, et al.
  • Journal Title: Cancer Immunology, Immunotherapy Volume: 61 Pages: 2143-2152
  • DOI: 10.1007/s00262-012-1275-8
  • Peer Reviewed
• [Presentation] Combination of low-dose and intermittent chemotherapy with cyclophosphamide and gemcitabine restores efficacy of anti-CD137 antibody therapy at the late tumor-bearing state (2014)
  • Author(s): Harada M, Tamada K, Harashima N
  • Organizer: 第43回日本免疫学会総会
  • Place of Presentation: 国立京都国際会館（京都市）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] HIF-2の阻害はヒト膵がん細胞のTRAIL感受性を増強する (2014)
  • Author(s): 原嶋奈々江、波里瑶子、門馬浩行、秋元美穂、竹永啓三、田島義証、原田守
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] ABT-263はヒト前立腺癌PC3細胞のドセタキセル感受性を増強する (2014)
  • Author(s): 玉木宏樹、原嶋奈々江、原田守
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 可溶性ST2は炎症性のがん微小環境を修飾し膵臓がんの腫瘍血管新生と増殖を抑制する (2014)
  • Author(s): 秋元美穂、原田守、竹永啓三
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] ABT-263はヒト膵がん細胞のTRAILによるアポトーシスを増強する (2014)
  • Author(s): 波里瑶子、原嶋奈々江、門馬浩行、田島義証、原田守
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] シイタケ菌糸体抽出物とgemcitabineの併用はTregとMDSCを抑制することで相乗的な抗腫瘍効果を発揮す (2014)
  • Author(s): 石川悟、和知俊、松井保公、山口博史、原田
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Pifithrin-, an inhibitor of HSP70, can increase the antitumor effects of hyperthermia against human prostate cancer cells (2014)
  • Author(s): Mamoru Harada
  • Organizer: 、The 6th ACHO & the 31st JCTM
  • Place of Presentation: 福井県民ホールAOSSA（福井市）
  • Year and Date: 2014-09-04 – 2014-09-06
  • Invited
• [Presentation] 抗がん剤やBRMによる免疫抑制の軽減と抗がんＴ細胞応答の誘導 (2014)
  • Author(s): 原田守
  • Organizer: 第52回日本癌治療学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-08-28 – 2014-08-30
  • Invited
• [Presentation] ：低酸素誘導因子 HIF 阻害によるヒト膵癌細胞のTRAIL感受性の増強 (2014)
  • Author(s): 原嶋奈々江、門馬浩行、波里瑶子、秋元美穂、竹永啓三、原田守
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: ひめぎんホール（松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Bcl-2 family 阻害剤によるヒト膵癌細胞のTRAIL抵抗性の克服 (2014)
  • Author(s): 波里瑶子、原嶋奈々江、門馬浩行、田島義証、原田守
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: ひめぎんホール（松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] ヒト膵癌細胞に対するTRAILとchloroquine の併用効果の検討 (2014)
  • Author(s): 門馬浩行、原嶋奈々江、波里瑶子、田島 義証、原田守
  • Organizer: 第18回日本がん免疫学会
  • Place of Presentation: ひめぎんホール（松山市）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Poly(I:C)トランスフェクションによるROS産生を伴った癌細胞死誘導とインターフェロン制御分子の関与 (2013)
  • Author(s): 原嶋奈々江、岡野慎士、原田守
  • Organizer: 第17回日本がん免疫学会
  • Place of Presentation: 全日空ホテル（宇部）
• [Presentation] HSP70阻害剤pifithrin-muがPanc-1膵癌細胞に対するTRAIL誘導性アポトーシスを増強する機序 (2013)
  • Author(s): 門馬浩行、原嶋奈々江、波里瑶子、田島 義証、原田守
  • Organizer: 第17回日本がん免疫学会
  • Place of Presentation: 全日空ホテル（宇部）
• [Presentation] 低用量 chemotherapyと抗CD137抗体の併用により誘導される持続的な抗腫瘍免疫応答 (2013)
  • Author(s): 頓宮美樹、原嶋奈々江、山田高也、岡野慎士、玉田耕治、原田守
  • Organizer: 第17回日本がん免疫学会
  • Place of Presentation: 全日空ホテル（宇部）
• [Presentation] Persistent antitumor immune response after the combination therapy with low-dose chemotherapy and anti-CD137 (4-1BB) antibody (2013)
  • Author(s): Tongu M, Harashima N, Yamada T, Okano S, Tamada K
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Restoration of the TRAIL susceptibility of human pancreatic cancer cells by inhibition (2013)
  • Author(s): Harashima N, Hari Y, Monma H, Tajima Y, Harada M
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Mechanisms of an HSP70 inhibitor pifithrin-mu to enhance TRAIL-induced apoptosis of pancreatic cancer cells (2013)
  • Author(s): Monma H, Harashima N, Hari Y, Tajima Y, Harada M
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] CD4 T cell-mediated masking effects of the immunogenicity of tumor-associated antigens are qualitatively and quantitatively different depending on the individual antigens (2013)
  • Author(s): Okano S, Yamashita Y, Harashima N, Ikegami T, Yoshizumi T, Shirabe K, Harada M, Yoshikai Y, and Maehara Y
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] A novel HSP70 inhibitor pifithrin-mu enhances the antitumor effect of radiation on human prostate cancer. (2013)
  • Author(s): Sekihara K, Harashima N, Tamaki Y, Hieda Y, Uchida N, Inomata T, Harada M
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Long-lasting suppression of CT26 growth after low-dose chemotherapy with cyclophosphamide plus gemcitabine followed by anti-CD137 antibody. (2013)
  • Author(s): Harada M, Okano S, Tanada K, Harashima N
  • Organizer: 第42回日本免疫学会学術総会
  • Place of Presentation: 幕張メッセ（千葉）
• [Presentation] 膵臓癌細胞に対するTRAILとHSP70阻害剤pifithrin-mu併用による抗腫瘍効果。 (2012)
  • Author(s): 門馬浩行 他7名
  • Organizer: 日本膵臓癌学会
  • Place of Presentation: ホテルメトロポリタン山形（山形市）
• [Presentation] ヒト乳癌細胞お抗癌剤抵抗性におけるオートファジーの役割。 (2012)
  • Author(s): 稲尾瞳子 他7名
  • Organizer: 日本乳癌学会
  • Place of Presentation: 熊本市民会館(熊本市）
• [Presentation] Ploy(I:C)トランスフェクションによるヒト腎癌さいぼうでのROS賛成とアポトーシスの誘導 (2012)
  • Author(s): 原嶋奈々江 他2名
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 北海道大学学術交流会館（札幌市）
• [Presentation] シイタケ菌糸体抽出物の経口摂取は担癌に伴うTregの増加を抑制することでペプチドワクチンによるCTL活性を維持できる (2012)
  • Author(s): 石川悟 他5名
  • Organizer: 日本がん免疫学会
  • Place of Presentation: 北海道大学学術交流会館（札幌市）
• [Presentation] オートファジーの阻害はアジュヴァント受容体リガンドでpoly(I:C)による細胞死を増強する (2012)
  • Author(s): 原嶋奈々江 他3名
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館（札幌市）
• [Presentation] HSP70およびオートファジー阻害剤pifithrin-muの膵癌細胞に対するTRAIL誘導性アポトーシス増強効果。 (2012)
  • Author(s): 門馬浩行 他６名
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館（札幌市）
• [Presentation] 新規HSP70阻害剤であるpifithrin-muは、ヒト前立腺癌において温熱療法の抗腫瘍効果を増強する可能性がある。 (2012)
  • Author(s): 関原和正 他5名
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館（札幌市）
• [Presentation] 低用量cyclophosphamideとgemcitabine の間歇的投与による抗腫瘍Ｔ細胞のin vivo誘導。 (2012)
  • Author(s): 頓宮美樹 他5名
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館（札幌市）
• [Presentation] 免疫療法後のドーマント期にＴ細胞応答抵抗性癌細胞が新たに出現する。 (2012)
  • Author(s): 岡野慎士 他2名
  • Organizer: 日本癌学会
  • Place of Presentation: ロイトン札幌、さっぽろ芸文館（札幌市）
• [Book] Effects of metronomic chemotherapy on immunity, in “Metronomic chemotherapy” (eds) Bocci G, Francia G. (2014)
  • Author(s): Mamoru Harada
  • Total Pages: 13
  • Publisher: Springer
• [Remarks] 島根大学医学部免疫学ホームページ
  • URL: http://www.med.shimane-u.ac.jp/immunology/index.html
• [Remarks] 島根大学医学部 免疫学講座
  • URL: http://www.med.shimane-u.ac.jp/immunology/
• [Remarks] 島根大学医学部免疫学ホームページ
  • URL: http://www.med.shimane-u.ac.jp/immunology/index.html