Combined anti-cancer immunotherapy based on the ability of immune responses in aged hosts

• Project/Area Number: 17K07217
• 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: Harada Mamoru 島根大学, 学術研究院医学・看護学系, 教授 (50260716)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 免疫療法 / 加齢 / 化学療法 / 集学的がん治療 / 抗がん剤 / 癌 / 免疫学 / 老化

Outline of Final Research Achievements

The in vivo growth of murine colon carcinoma CT26 was more rapid in aged mice compared to young mice, and the serum levels of IL-6 were elevated in aged mice. In addition, aged mice showed lower response to anti-cancer vaccine by inactivated cancer cells compared to young mice. On the other hand, we examined the immune responses to murine renal carcinoma RENCA expressing human CA9 (hCA9) as a non-self antigen. As a result, young mice rejected RENCA/hCA9 and human CA9-recognizing CD8+ T cells and CD4+ T cells were induced in such mice. In addition, aged mice allowed RENCA/hCA9 to grow in vivo but combined immunotherapy with immune checkpoint blockade therapy with chemotherapy exerted significant antitumor effects even in aged mice.

Academic Significance and Societal Importance of the Research Achievements

本研究では、加齢担がん生体での有効な複合免疫療法の確立を目指した。加齢に伴い炎症性サイトカインが上昇し、担がん状態の場合さらに炎症状態が悪化する。また、加齢担がん生体では強力な化学療法を受けた後では骨髄抑制が生じ、抗がんT細胞を再賦活させる免疫チェックポイント抗体療法も効果を示さないかもしれない。研究の成果は、実臨床において、がん患者の大部分を占める中高年のがん患者に対して複合免疫療法を実施する場合の貴重な基盤的情報になり、高齢化が進む本邦における複合抗がん免疫療法の適応拡大に大いに貢献できると予想される。

Research Products

• [Journal Article] Anticancer Activity of ZnO Nanoparticles Against Human Small-Cell Lung Cancer in an Orthotopic Mouse Model. (2020)
  • Author(s): Tanino R, Amano Y, Tong X, Sun R, Tsubata Y, Harada M, Fujita Y, and Isobe T.
  • Journal Title: Molecular Cancer Therapeutics Volume: 19 Issue: 2 Pages: 502-512
  • DOI: 10.1158/1535-7163.mct-19-0018
  • Peer Reviewed
• [Journal Article] Pemetrexed Sensitizes Human Lung Cancer Cells to Cytotoxic Immune Cells (2020)
  • Author(s): Okimoto T, Kotani H, Iida Y, Koyanagi A, Tanino R, Tsubata Y, Isobe T, Harada M.
  • Journal Title: Cancer Sci. Volume: ー Issue: 6 Pages: 1910-1920
  • DOI: 10.1111/cas.14401
  • Peer Reviewed / Open Access
• [Journal Article] Different Sensitivities of Senescent Breast Cancer Cells to Immune Cell-Mediated Cytotoxicity (2019)
  • Author(s): Inao T, Kotani H, Iida Y, Kartika ID, Okimoto T, Tanino R, Shiba E, Harada M.
  • Journal Title: Cancer Sci. Volume: 110(9) Issue: 9 Pages: 2690-2699
  • DOI: 10.1111/cas.14116
  • NAID: 120007002176
  • Peer Reviewed / Open Access
• [Journal Article] Potential mechanisms of spontaneous regression in patients with B-cell lymphoma: the significance of co-stimulatory molecules in lymphoma cells. (2019)
  • Author(s): Komohara Y, Harada M.
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 59 Issue: 4 Pages: 207-210
  • DOI: 10.3960/jslrt.19026
  • NAID: 130007771311
  • Peer Reviewed
• [Journal Article] Chloroquine augments TRAIL-induced apoptosis and induces G2/M phase arrest in human pancreatic cancer cells (2018)
  • Author(s): Monma H, Iida Y, Moritani T, Okimoto T, Tanino R, Tajima Y, Harada M.
  • Journal Title: PLOS ONE Volume: 7 Issue: 3 Pages: e0193990-e0193990
  • DOI: 10.1371/journal.pone.0193990
  • NAID: 120006539383
  • Peer Reviewed / Open Access
• [Journal Article] Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer. (2018)
  • Author(s): Tanino R, Tsubata Y, Harashima N, Harada M, Isobe T.
  • Journal Title: Oncotarget Volume: 9 Issue: 24 Pages: 16807-16821
  • DOI: 10.18632/oncotarget.24704
  • Peer Reviewed / Open Access
• [Journal Article] Bcl-2 inhibition sensitizes triple-negative humna breast cancer cells to doxorubicin. (2018)
  • Author(s): Inao T, Iida Y, Moritani T, Okimoto T, Tanino R, Kotani H, Harada M.
  • Journal Title: Oncotarget Volume: 9 Issue: 39 Pages: 25545-25556
  • DOI: 10.18632/oncotarget.25370
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma. (2017)
  • Author(s): 1.Minami T, Matsumura N, Sugimoto K, Shimizu N, De Velasco M, Nozawa M, Yoshimura K, Harashima N, Harada M, Uemura H.
  • Journal Title: Int Immunopharmacol. Volume: 44 Pages: 197-202
  • DOI: 10.1016/j.intimp.2017.01.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression (2017)
  • Author(s): Harashima Nanae、Takenaga Keizo、Akimoto Miho、Harada Mamoru
  • Journal Title: Oncotarget Volume: 8 Issue: 26 Pages: 42887-42900
  • DOI: 10.18632/oncotarget.17157
  • NAID: 120006532063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Contrasting effects of cyclophosphamide on anti-CTLA-4 blockade therapy in two tumor mouse models. (2017)
  • Author(s): Iida Y, Harashima N, Motoshima T, Komohara Y, Eto M, Harada M.
  • Journal Title: Cancer Science, Volume: 108 Issue: 10 Pages: 1974-1984
  • DOI: 10.1111/cas.13337
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Local injection of CCL19-expressing mesenchymal stem cells augments the therapeutic efficacy of anti-PD-L1 antibody by promoting infiltration of immune cells. (2019)
  • Author(s): Iida Y, Yoshikawa R, Murata A, Kotani H, Matsuzaki Y, Harada M.
  • Organizer: 第23回がん免疫学会
• [Presentation] Different sensitivities of senescent breast cancer cells to immune cell-mediated cytotoxicity (2019)
  • Author(s): 原田守, 小谷仁司、飯田雄一、稲尾瞳子
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Supplementation of L-arginine augments antitumor effects induced by chemotherapy and immune checkpoint blockade therapy. (2019)
  • Author(s): 佐藤悠介, 小谷仁司、飯田雄一、谷浦隆仁、原田守。
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Senescent breast cancer cells induced by doxorubicin or the CDK4/6 inhibitor abemaciclib show different sensitivities to immune cell-mediated cytotoxicity. (2019)
  • Author(s): Harada M, Kotani H, Iida Y.
  • Organizer: 第48回日本免疫学会総会
• [Presentation] Identification of a candidate that suppresses the differentiation of naïve helper T cells to regulatory T cells via screening of herbal crude drugs. (2019)
  • Author(s): Kotani H, Iida Y, Harada M.
  • Organizer: 第48回日本免疫学会総会
• [Presentation] Local deliver of CCL19-expressing mesenchymal stromal cells augments the therapeutic efficacy by anti-PD-L1 blockade antibody via promoting infiltration of immune cells. (2019)
  • Author(s): Iida Y, Yoshikawa R, Murata A, Kotani H, Matsuzaki Y, Harada M.
  • Organizer: 第48回日本免疫学会総
• [Presentation] p53遺伝子変異を有するトリプルネガティブ乳癌細胞株に対するdoxorubicinとBcl-2 阻害剤（ABT-199）の併用効果 (2018)
  • Author(s): 稲尾瞳子、原田守
  • Organizer: 第118回日本外科学会学術総会
• [Presentation] Doxorubicinはヒト乳がん細胞にsenescenceを誘導し細胞傷害性免疫細胞に対する感受性を増強させる (2018)
  • Author(s): 稲尾瞳子、原田守
  • Organizer: 第26回日本乳がん学会
• [Presentation] Doxorubicin induces cellular senescence in human breast cancer cells and sensitizes them to cytotoxic T-lymphocytes. (2018)
  • Author(s): Inao T, Iida Y, Kotani H, Harada M.
  • Organizer: San Antonio Breast Cancer Symposium.
  • Int'l Joint Research
• [Presentation] 抗がん剤pemetrexedでsenescence に陥ったヒト肺がん細胞は細胞傷害性T細胞に傷害されやすい (2018)
  • Author(s): 原田守、沖本民生、谷野良輔、飯田雄一、礒部威
  • Organizer: 第22回がん免疫学会
• [Presentation] 間葉系幹細胞の腫瘍局所残存性を利用した新規抗がん免疫療法のマウスモデルの確立 (2018)
  • Author(s): 飯田雄一、吉川倫太郎、松崎有未、原田守
  • Organizer: 第22回がん免疫学会
• [Presentation] Anti-cancer drugs induce senescence in cancer cells and increase their sensitivity to CAR-T cells (2018)
  • Author(s): Harada M, Okimoto T, Inao T, Tanino R, iida Y, Isobe T.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Chemotherapy-induced senescent cancer cells are good targets for T cell-based anti-cancer immunotherapy (2018)
  • Author(s): Harada M, Kotani H, Iida Y.
  • Organizer: 第47回日本免疫学会総会
• [Presentation] Local delivery of CCL19-expressing mesenchymal stromal cells suppresses the tumor growth via promoting infiltration of immune cells. (2018)
  • Author(s): Iida Y, Yoshikawa R, Murata A, Matsuzaki Y, Harada M
  • Organizer: 第47回日本免疫学会総会
• [Presentation] Pros and cons of cyclophosphamide in anti-CTLA-4 antibody-treated different tumor mouse models (2017)
  • Author(s): 飯田雄一、原嶋奈々江、元島崇信、菰原義弘、江藤正俊、原田守
  • Organizer: 第21回日本がん免疫学会
• [Presentation] Contrasting interaction between cyclophosphamide and anti-CTLA-4 therapy in different mouse tumor models. (2017)
  • Author(s): 原田守、飯田雄一、原嶋奈々江、元島崇信、菰原義弘、江藤正俊
  • Organizer: 第76回日本癌学会
• [Presentation] トリプルネガティブ乳癌細胞株に対するdoxorubicinとBcl-2 阻害剤の併用効果 (2017)
  • Author(s): 稲尾瞳子、原嶋奈々江、原田守
  • Organizer: 第25回日本乳癌学
• [Presentation] Pemetrexed-resistant non-small cell lung cancer cell lines have novel drug-resistance mechanisms. (2017)
  • Author(s): Tanino R, Tsubata Y, Harashima N, Harada M, Isobe T.
  • Organizer: 世界肺癌学会(WCLC2017)
  • Int'l Joint Research
• [Remarks] 島根大学医学部免疫学講座
  • URL: https://www/med.shimane-u.ac.jp/immunology/
• [Remarks] 研究業績
  • URL: http://www.med.shimane-u.ac.jp/immunology