Development of effective immunotherapy by combining interventions on key points in the anti-tumor immune network

2013 Fiscal Year Final Research Report

• Project/Area Number: 23240128
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor immunology
• Research Institution: Keio University
• Principal Investigator: KAWAKAMI Yutaka 慶應義塾大学, 医学部, 教授 (50161287)
• Co-Investigator(Renkei-kenkyūsha): KUDO Chie 慶應義塾大学, 医学部, 講師 (90424126) ; FUJITA Tomonobu 慶應義塾大学, 医学部, 助教 (20199334) ; SAKURAI Toshiharu 慶應義塾大学, 医学部, 助教 (20101933) ; TSUKAMOTO Nobuo 慶應義塾大学, 医学部, 助教 (20407117) ; OHTA Shigeki 慶應義塾大学, 医学部, 講師 (20365406) ; YAGUCHI Tomonori 慶應義塾大学, 医学部, 助教 (40424163)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: がん免疫療法 / 腫瘍抗原 / 樹状細胞 / T細胞 / 免疫抑制 / 免疫チェックポイント阻害

Research Abstract

In this sturdy, we have attempted to develop effective cancer immunotherapy by combining immune-regulating interventions on multiple important points in the cancer related positive and negative immune responses. We have developed and evaluated the following interventions; 1) interventions to induce immunogenic cancer cell death, 2) cancer antigens expressed in cancer stem cells which are resistant to chemotherapy, 3) interventions to stimulate antigen presenting dendritic cells for anti-cancer T-cell activation, 4) interventions to activate anti-cancer T-cells, 5) interventions to reverse cancer-induced immunosuppression. Using mouse tumor models, we have evaluated cancer immunotherapies in which the above interventions are appropriately combined, particularly with immune-checkpoint blockade therapies. These results may lead to development of more effective cancer immunotherapies through evaluation in the future clinical trials.

Research Products

• [Journal Article] Induction of immunoregulatory CD271+ cells by metastatic tumor cells that express human endogenous retrovirus (2014)
  • Author(s): Kudo-Saito C, Yura M, Yamamoto R, Kawakami Y
  • Journal Title: H Cancer Res Volume: 74(5) Pages: 1361-70
  • DOI: 10.1158/0008-5472.CAN-13-1349
  • Peer Reviewed
• [Journal Article] TGF-β1 in tumor microenvironments induces immunosuppression in the tumors and sentinel lymph nodes and promotes tumor progression (2014)
  • Author(s): Nakamura S, Yaguchi T, Kawamura N, Kobayashi A, Sakurai T, Higuchi H, Takaishi H, Hibi T, Kawakami Y
  • Journal Title: J Immunother Volume: 37(2) Pages: 63-72
  • DOI: 10.1097/CJI.0000000000000011
  • Peer Reviewed
• [Journal Article] Targeting FSTL1 prevents tumor bone metastasis and consequent immune dysfunction (2013)
  • Author(s): Kudo-Saito C, Fuwa T, Murakami K, Kawakami Y
  • Journal Title: Cancer Res Volume: 73(20) Pages: 6185-6193
  • DOI: 10.1158/0008-5472.CAN-13-1364
  • Peer Reviewed
• [Journal Article] Immunochemoradiotherapy for Patients with Oral Squamous Cell Carcinoma : Augmentation of OK-432-Induced Helper T Cell 1 Response by 5-FU and X-ray Irradiation (2013)
  • Author(s): Tano T, Okamoto M, Kan S, Bando T, Goda H, Nakashiro K, Shimodaira S, Koido S, Homma S, Fujita T, Sato M, Yamashita N, Hamakawa H, Kawakami Y
  • Journal Title: Neoplasia Volume: 15(7) Pages: 805-814
  • DOI: 10.1593/neo.13488
  • Peer Reviewed
• [Journal Article] Improvement of cancer immunotherapy by combining molecular targeted therapy (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Iwata-Kajihara T, Nakamura S, Miyzaki J, Kawamura N, Hoon Park J, Popivanova B, Tsujikawa T
  • Journal Title: Frontiers in Oncology Volume: 36 Pages: 1-7
  • DOI: 10.3389/fonc.2013.00136
  • Peer Reviewed
• [Journal Article] Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma (2013)
  • Author(s): Tsujikawa T, Yaguchi T, Ohmura G, Ohta S, Kobayashi A, Kawamura N, Fujita T, Nakano H, Shimada T, Takahashi T, Nakao R, Yanagisawa A, Hisa Y, Kawakami Y
  • Journal Title: Int J Cancer Volume: 132(12) Pages: 2755-2766
  • DOI: 10.1002/ijc.27966
  • Peer Reviewed
• [Journal Article] Growth inhibition and apoptosis by an active component of OK-432, a streptococcal agent, via Toll-like receptor 4 in human head and neck cancer cell lines (2012)
  • Author(s): Tano T, Okamoto M, Kan S, Nakashiro K, Shimodaira S, Yamashita N, Kawakami Y, Hamakawa H
  • Journal Title: Oral Oncol Volume: 48(8) Pages: 678-685
  • DOI: 10.1016/j.oraloncology
  • Peer Reviewed
• [Journal Article] CCL2 is critical for immunosuppression to promote cancer metastasis (2012)
  • Author(s): Kudo-Saito C, Shirako H, Ohike M, Tsukamoto N, Kawakami Y
  • Journal Title: Clin Exp Metastasis Volume: 30(4) Pages: 393-405
  • DOI: 10.1007/s10585-012-9545-6
  • Peer Reviewed
• [Journal Article] Cancer-testis antigen BORIS is a novel prognostic marker for patients with esophageal cancer (2012)
  • Author(s): Okabayashi K, Fujita T, Miyazaki J, Okada T, Iwata T, Hirao N, Noji S, Tsukamoto N, Goshima N, Hasegawa H, Takeuchi H, Ueda M, Kitagawa Y, Kawakami Y
  • Journal Title: Cancer Sci Volume: 103(9) Pages: 1617-1624
  • DOI: 10.1111/j.1349-7006.2012.02355.x
  • Peer Reviewed
• [Journal Article] Immune suppression and resistance mediated by constitutive activation of Wnt/β-catenin signaling in human melanoma cells (2012)
  • Author(s): Yaguchi T, Goto Y, Kido K, Mochimaru H, Sakurai T, Tsukamoto N, Kudo-Saito C, Fujita T, Sumimoto H, Kawakami Y
  • Journal Title: J Immunol Volume: 189(5) Pages: 2110-2117
  • DOI: 10.4049/jimmunol.1102282
  • Peer Reviewed
• [Journal Article] Enhanced Cancer Immunotherapy Using STAT3-Depleted Dendritic cells with High Th1-Inducing Ability and Resistance to Cancer Cell-Derived Inhibitory Factors (2011)
  • Author(s): Iwata-Kajihara T, Sumimoto H, Kawamura N, Ueda R, Takahashi T, Mizuguchi H, Miyagishi M, Takeda K, Kawakami Y
  • Journal Title: J Immunol Volume: 187(1) Pages: 27-36
  • DOI: 10.4049/jimmunol.1002067
  • Peer Reviewed
• [Journal Article] Immunosuppression through constitutively activated NF-κB signaling in human ovarian cancer and its reversal by a NF-κB inhibitor
  • Author(s): Nishio H, Yaguchi T, Sugiyama J, SumimotoH, UmezawaK, Iwata T, Susumu N, Fujii T, KawamuraN, KobayashiA, Park JH, Aoki D, Kawakami Y
  • Journal Title: British Journal of Cancer Volume: (in press)
  • Peer Reviewed
• [Presentation] Different immunoenvironments among cancer patients-Possible Biomarkers and modification for effective cancer treatments (2013)
  • Author(s): Kawakami Y, Xu M, Nagumo H, Fujita T, Okamoto M, Sakurai T, Noji S, Sugiyama J, Hayakawa T, Nishio H, Yaguchi T
  • Organizer: Cold Spring Harbor Conferences Asia, Tumor Immunolgy & Immunotherapy
  • Place of Presentation: Suzhou Dushu Lake Conference Center Suzhou, China
  • Year and Date: 2013-10-29
• [Presentation] Mechanisims for cancer induced immunosuppresiono in tumor associated microenvironment and their reversal by targeting altered signaling pathways in cancer cells and immune cells (2012)
  • Author(s): Kawakami Y
  • Organizer: CSH Asia/ICMS Joint Conference on Tumor Microenvironment
  • Place of Presentation: Suzhou Dushu Lake Conference Center, Suzhou, China
  • Year and Date: 2012-11-16
• [Presentation] Reversal of Multiple Cancer Induced Immunosuppressive Cascades by Molecular Targeted Therapy for Effective Immunotherapy (2012)
  • Author(s): Kawakami Y
  • Organizer: The 7th International Cancer Vaccine Symposium
  • Place of Presentation: Convitto Dlla Calza, Florence, Italy
  • Year and Date: 2012-09-12
• [Presentation] Role of IL6/IL8-NF-KB AXIS in the Immunosuppression and resistance to immunotherapy (2011)
  • Author(s): Kawakami Y, Nishio H, Yaguchi T, Kawase Y, Ohizumi A, Noji S, Sakurai T, Umezawa K, Fujita T
  • Organizer: 26th Annual Meeting Society for Immunotherapy of Cancer
  • Place of Presentation: North Bethesda, MD, USA
  • Year and Date: 2011-11-04
• [Book] Roles of signaling pathways in cancer cells and immune cells in generation of immunosuppressive tumor associated microenvironments. in "The Tumor Immunoenvironment" Eds, Shurin M, Malyguine A, Umansky V (2013)
  • Author(s): Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, Tanaka M, Kamijuku H, Tsujikawa T, Kawamura N
  • Total Pages: 307-323
  • Publisher: Springer Science
• [Book] Human tumor antigens recognized by T cells and their implications for cancer immunotherapy in "Innate immune regulation and Cancer immunotherapy", Wang RF ed (2011)
  • Author(s): Ueda R, Yaguchi T, Kawakami Y
  • Total Pages: 335-345
  • Publisher: Springer Science. Business Media, New York USA
• [Remarks]
  • URL: http://keiocancer.com/