Restoration of immune susceptibility to cancer cells regulated by autophagy and hypoxic responses

• Project/Area Number: 25430150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Shimane University
• Principal Investigator: HARASHIMA Nanae 島根大学, 医学部, 助教 (60345311)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 低酸素 / 癌 / 免疫 / 治療抵抗性 / オートファジー / アポトーシス

Outline of Final Research Achievements

In the human pancreatic cancer cells which showed resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as an anticancer drug, I investigated to restore the sensitivity to TRAIL and elucidate its cellular mechanisms. Pifithrin-mu, an inhibitor of autophagy or ABT-263, a Bcl-2 family inhibitor which targets Bcl-2, Bcl-xL, and Bcl-w significantly enhanced the sensitivity to TRAIL in human pancreatic cancer cells. Knockdown of HIF-2alpha, but not HIF-1alpha, using siRNA increased the susceptibility of pancreatic cancer cells to TRAIL via decreased the expression of anti-apoptotic protein survivin, and induced antitumor effects. These results suggest that inhibition of HIF-2alpha, autophagy, or anti-apoptotic molecules can enhance the efficacy of immune therapies to cancers.

Research Products

• [Journal Article] Detection of an immunogenic HERV-E envelope with selective expression in clear cell kidney cancer (2016)
  • Author(s): Cherkasova E., Scrivani C., Doh S., Weisman Q., Takahashi Y., Harashima N., Yokoyama H., Srinivasan R., Linehan WM., Lerman MI., and Childs RW.
  • Journal Title: Cancer Research Volume: 76 (8) Issue: 8 Pages: 2177-2185
  • DOI: 10.1158/0008-5472.can-15-3139
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The roles of ROS and caspases in TRAIL-Induced apoptosis and necroptosis in human pancreatic cancer cells (2015)
  • Author(s): Zhang M, Harashima N, Moritani T, Huang W, Harada M.
  • Journal Title: PLoS One Volume: 10 (5) Issue: 5 Pages: e0127386-e0127386
  • DOI: 10.1371/journal.pone.0127386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of programmed death ligand 1-derived peptides capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma (2015)
  • Author(s): Minami T., Minami T., Shimizu N., Yamamoto Y., De Velasco MA., Nozawa M., Yoshimura K., Harashima N., Harada M., Uemura H.
  • Journal Title: Journal of Immunotherapy Volume: 38 (7) Issue: 7 Pages: 285-291
  • DOI: 10.1097/cji.0000000000000090
  • Peer Reviewed
• [Journal Article] Bcl-xL inhibition by molecular-targeting drugs sensitizes human pancreatic cancer cells (2015)
  • Author(s): Hari Y., Harashima N., Tajima Y., Harada M.
  • Journal Title: Oncotarget Volume: 6 (39) Issue: 39 Pages: 41902-41915
  • DOI: 10.18632/oncotarget.5881
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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 Science Volume: 106 Issue: 1 Pages: 9-17
  • DOI: 10.1111/cas.12568
  • NAID: 120005982740
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: International Immunopharmacology Volume: 26 Issue: 1 Pages: 133-138
  • DOI: 10.1016/j.intimp.2015.03.023
  • Peer Reviewed / Open Access
• [Journal Article] Transfection of poly(I:C) can induce ROS-triggered apoptosis and IFN--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: Molecular Cancer Volume: 13 Issue: 1 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): Tamaki H, Harashima N, Hiraki M, Aichi N, Nishimura N, Shiina H, Naora K, Harada M.
  • Journal Title: Oncotarget Volume: 5 (22) Pages: 11399-11412
  • 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 Issue: 1 Pages: 59-65
  • DOI: 10.1016/j.intimp.2014.02.018
  • Peer Reviewed / Open Access
• [Journal Article] The HSP70 and autophagy inhibitor pifithrin-mu enhances the antitumor effects of TRAIL on human pancreatic cancer (2013)
  • Author(s): Monma H, Harashima N, et al.
  • Journal Title: Mol Cancer Ther Volume: 12 Issue: 4 Pages: 341-351
  • DOI: 10.1158/1535-7163.mct-12-0954
  • 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 Issue: 11 Pages: e78772-e78772
  • DOI: 10.1371/journal.pone.0078772
  • Peer Reviewed
• [Presentation] HIF-2alpha, but not HIF-1alpha, determines immune resistance of pancreatic cancer cells to TRAIL and T cells via survivin (2015)
  • Author(s): Harada M., Harashima N.
  • Organizer: 第44回日本免疫学会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2015-11-18
• [Presentation] Bcl-xL inhibition sensitizes human pancreatic cancer cells to TRAIL (2015)
  • Author(s): 波里瑶子、原嶋奈々江、田島義証、原田守
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知）
  • Year and Date: 2015-10-08
• [Presentation] HIF-2alpha regulates susceptibility of human pancreatic cancer cells to TRAIL- and T cell-mediated cytotoxicity via survivin (2015)
  • Author(s): 原嶋奈々江、秋元美穂、竹永啓三、原田守
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知）
  • Year and Date: 2015-10-08
• [Presentation] Regulatory roles of HIF-2alpha and survivin in TRAIL- and gannma-deltaT cell-mediated cytotoxicity of human pancreatic cancer cells (2015)
  • Author(s): Harashima N., Harada M.
  • Organizer: 19th JACI & 23rd MMCB, がん免疫療法・マクロファージ国際会議2015
  • Place of Presentation: 東京大学（東京）
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [Presentation] The role of ROS and caspases in TRAIL-induced apoptosis and necroptosis in human pancreatic cancer cells (2015)
  • Author(s): Harada M., Harashima N.
  • Organizer: 19th JACI & 23rd MMCB, がん免疫療法・マクロファージ国際会議2015
  • Place of Presentation: 東京大学（東京）
  • Year and Date: 2015-07-09
  • Int'l Joint Research
• [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
  • 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-2alpha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、秋元美穂、竹永啓三、原田守
  • Organizer: 第12回がんとハイポキシア研究会
  • Place of Presentation: ホテルマリターレ創世佐賀（佐賀市）
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] Bcl-2 family inhibitors effectively sensitize human pancreatic cancer cells to TRAIL (2014)
  • Author(s): Hari Y, Harashima N, Kidani A, Hayashi H, Kawabata Y, Harada M, Yano S, Tajima Y
  • Organizer: 45th Anniversary Meeting of APA (American pancreatic association) /JPS(日本膵臓学会)
  • Place of Presentation: Hapuna Beach Prince Hotel, Big Island, Hawaii, U.S.A.
  • Year and Date: 2014-11-05 – 2014-11-08
• [Presentation] Autophagy inhibitors enhance TRAIL-Induced antitumor effects on human pancreatic cancer cells (2014)
  • Author(s): Monma H, Harashima N, Hari Y, Kishi S, Tajima Y, Harada M
  • Organizer: 45th Anniversary Meeting of APA (American pancreatic association) /JPS(日本膵臓学会)
  • Place of Presentation: Hapuna Beach Prince Hotel, Big Island, Hawaii, U.S.A.
  • Year and Date: 2014-11-05 – 2014-11-08
• [Presentation] ABT-263 sensitizes PC3 prostate cancer cells to docetaxel (2014)
  • Author(s): 玉木宏樹、原嶋奈々江、原田守
  • Organizer: 第73回日本癌学会
  • Place of Presentation: パシフィコ横浜（横浜市、神奈川）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Bcl-2 family inhibitor ABT-263 unveils the resistance to TRAIL-induced apoptosis in human pancreatic cancer cells (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
  • Place of Presentation: パシフィコ横浜（横浜市、神奈川）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Inhibition of HIF-2alpha sensitizes human pancreatic cancer cells to TRAIL (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
  • Place of Presentation: パシフィコ横浜（横浜市、神奈川）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Bcl-2 family阻害剤併用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、愛媛）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] 低酸素誘導因子hypoxia-inducible factor阻害によるヒト膵癌細胞のTRAIL抵抗性の増強 (2014)
  • Author(s): 原嶋奈々江、波里瑶子、門馬浩行、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、愛媛）
  • 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、愛媛）
  • Year and Date: 2014-07-30 – 2014-08-01
• [Presentation] Autophagy阻害剤を用いたヒト膵癌に対するTRAILの抗腫瘍効果増強の検討 (2014)
  • Author(s): 門馬浩行， 原田守， 波里瑶子， 原嶋奈々江， 高井清江， 木谷昭彦， 林彦多， 川畑康成， 矢野誠司， 田島義証
  • Organizer: 第69回 日本消化器外科学会総会
  • Place of Presentation: ホテルハマツ/郡山市民文化センター（郡山市、福島）
  • Year and Date: 2014-07-16 – 2014-07-18
• [Presentation] Bcl-2ファミリー阻害剤併用によるヒト前立腺癌細胞のDocetaxel感受性の増強 (2014)
  • Author(s): 玉木宏樹、西村信弘、原嶋奈々江、原田守、直良浩司
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: ホテル日航熊本、鶴屋ホール、熊本大学他（熊本）
• [Presentation] 膵癌細胞に対するTRAILと新規HSP70阻害剤pifithrin-muの併用効果と作用機序 (2013)
  • Author(s): 門馬浩行, 原嶋奈々江, 木谷昭彦, 西健, 川畑 康成, 矢野誠司, 田島 義証
  • Organizer: 第44回日本膵臓学会
  • Place of Presentation: 仙台国際センター（仙台）
• [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: ANAクラウンプラザホテル宇部（山口）
• [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 (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: ANAクラウンプラザホテル宇部（山口）
• [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その活性化経路 (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: ANAクラウンプラザホテル宇部（山口）
• [Presentation] Persistent antitumor immunity after the combination therapy with low-dose chemotherapy and anti-CD137 (4-1BB) antibody (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72回日本癌学会
  • 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 of Bcl-xL (2013)
  • Author(s): 原嶋奈々江、波里瑶子、門馬浩行、田島義証、原田守
  • Organizer: 第72回日本癌学会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Mechanisms of an HSP-70 inhibitor pifithrin-mu to enhance TRAIL-induced apoptosis of pancreatic cancer cells (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72回日本癌学会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] A novel HSP-70 inhibitor pifithrin-mu enhances the antitumor effect of radiation on human prostate cancer (2013)
  • Author(s): 関原和正、原嶋奈々江、内田伸恵、猪俣泰典、原田守
  • Organizer: 第72回日本癌学会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] Poly(I:C), an innate adjuvant receptor ligand, can induce the antitumor effects on human breast cancer cells (2013)
  • Author(s): Touko Inao, Nanae Harashima, Yutaka Yamamoto, Mamoru Harada, Hirotaka Iwase
  • Organizer: 36th Annual SABCS
  • Place of Presentation: San Antonio (U.S.A)
• [Presentation] Long-lasting suppression of CT26 growth after low-dose chemotherapy with cyclophosphamide plus gemcitabine, followed by anti-CD137 antibody (2013)
  • Author(s): 原田守、岡野慎士、玉田耕治、原嶋奈々江
  • Organizer: 第42回日本免疫学会
  • Place of Presentation: 幕張メッセ（千葉県幕張市）