Development of chemo-immunotherapy based on the characterization of tumor-infiltrating myeloid-derived suppressor cells

• Project/Area Number: 16K08752
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Aoki Kazunori 国立研究開発法人国立がん研究センター, 研究所, 分野長 (60270675)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 化学免疫療法 / 骨髄由来抑制細胞 / サイトカイン / シングルセル解析 / 肺がん / 間質線維芽細胞 / 免疫学

Outline of Final Research Achievements

To develop the effective chemo-immunotherapy, we focused on the characterization of tumor-infiltrating myeloid-derived suppressor cells (MDSC), which are considered as a major resistance factor against the antitumor induction by chemo-immunotherapy.
We identified a specific subtype in tumor-infiltrating MDSCs and elucidated the characteristics of the gene expression profile. Then, we found that the cancer-associated fibroblasts recruited the MDSC into tumors by production of MDSC-related cytokines such as CXCL6. Finally, we showed that the combination of chemotherapy and the depletion of MDSC enhanced antitumor immunity and induce synergistic antitumor effect in mouse model.

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害剤が多くのがん種に対して有効性を示すが、70-80％が抵抗性を示す。そこで、現在、化学療法と免疫療法の併用などの複合的免疫療法の開発が期待されている。
本研究では、化学免疫療法の抵抗因子である骨髄由来抑制細胞(MDSC)に着目して、腫瘍内に浸潤する特徴的なサブタイプを同定、またMDSCの腫瘍への浸潤機構を明らかとした。さらに、MDSCを抑制することにより化学免疫療法の効果が増強できることを示した。これらの研究成果は、今後有効な化学免疫療法の開発に結びつけるうえでの重要な基礎データとなる。

Research Products

• [Journal Article] Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery (2019)
  • Author(s): Narumi Kenta、Miyakawa Reina、Shibasaki Chihiro、Henmi Marina、Mizoguchi Yukihiro、Ueda Ryosuke、Hashimoto Hisayoshi、Hiraoka Nobuyoshi、Yoshida Teruhiko、Aoki Kazunori
  • Journal Title: Scientific Reports Volume: 9 Issue: 1
  • DOI: 10.1038/s41598-019-41724-x
  • Peer Reviewed / Open Access
• [Journal Article] Pre-immunization of donor lymphocytes with GITR agonistic antibody enhances antitumor immunity in autologous hematopoietic stem cell transplantation (2019)
  • Author(s): Henmi Marina、Shibasaki Chihiro、Mizoguchi Yukihiro、Hirata Aya、Sawai Eri、Narumi Kenta、Aoki Kazunori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 509 Issue: 1 Pages: 96-101
  • DOI: 10.1016/j.bbrc.2018.12.069
  • Peer Reviewed
• [Journal Article] Intratumoral IFN-α gene delivery reduces tumor-infiltrating regulatory T cells through the downregulation of tumor CCL17 expression (2018)
  • Author(s): Hirata Aya、Hashimoto Hisayoshi、Shibasaki Chihiro、Narumi Kenta、Aoki Kazunori
  • Journal Title: Cancer Gene Therapy Volume: - Issue: 9-10 Pages: 334-343
  • DOI: 10.1038/s41417-018-0059-5
  • Peer Reviewed
• [Journal Article] がん免疫療法開発のガイダンス2016 (2018)
  • Author(s): 青木一教、中釡斉
  • Journal Title: 臨床免疫・アレルギー科 Volume: 69 Pages: 207-211
• [Journal Article] A tumor-targeting adenovirus with high gene transduction efficiency for primary pancreatic cancer and ascites cells (2017)
  • Author(s): Nagasato M, et al.
  • Journal Title: Anticancer Research Volume: 37 Issue: 7 Pages: 3599-3506
  • DOI: 10.21873/anticanres.11730
  • Peer Reviewed
• [Journal Article] Correlation between NKG2D ligand expression and antitumor effect of protein bound polysaccharide-K in tumor-bearing mouse models (2017)
  • Author(s): Konagai Ａ, et al.
  • Journal Title: Anticancer Research Volume: 37 Issue: 8 Pages: 4093-4101
  • DOI: 10.21873/anticanres.11796
  • Peer Reviewed
• [Journal Article] Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors (2017)
  • Author(s): Yamamoto Ｙ et al.
  • Journal Title: Cancer Medicine Volume: 6 Issue: 10 Pages: 2385-2397
  • DOI: 10.1002/cam4.1185
  • Peer Reviewed
• [Journal Article] The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy (2017)
  • Author(s): Shoji H, Heike Y, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Hamaguchi T.
  • Journal Title: OncoTarget Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in genetic modification of adenovirus vectors for cancer treatment (2017)
  • Author(s): Y. Yamamoto, M. Nagasato, T. Yoshida, K. Aoki
  • Journal Title: Cancer Sci Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] がん免疫微小環境のシングルセル解析で何がわかってきたか (2017)
  • Author(s): 青木一教
  • Journal Title: 実験医学 Volume: ３５ Pages: 552-556
• [Journal Article] Pretreatment Immune Status Correlates with Progression-Free Survival in Chemotherapy-Treated Metastatic Colorectal Cancer Patients. (2016)
  • Author(s): Tada K, Kitano S, Shoji H, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Okita N, Takashima A, Kato K, Yamada Y, Katayama N, Boku N, Heike Y, Hamaguchi T.
  • Journal Title: Cancer immunology research Volume: 4(7) Issue: 7 Pages: 592-599
  • DOI: 10.1158/2326-6066.cir-15-0298
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] The role of cancer-associated fibroblasts in immune suppressive microenvironment of lung cancer (2019)
  • Author(s): Eri Sawai, Makiko Yamashita, Aya Hirata, Yukihiro Mizoguchi, Makoto Miyazaki, Genichiro Ishii, Kazunori Aoki
  • Organizer: 11th AACR-JCA Joint Conference
  • Int'l Joint Research
• [Presentation] Tumor immune microenvironment in pancreatic cancer (2018)
  • Author(s): Kazunori Aoki
  • Organizer: Asan Cancer Institute Symposium
  • Int'l Joint Research / Invited
• [Presentation] The immunological role of pancreatic cancer-associated fibroblasts to construct immunosuppressive microenvironment (2018)
  • Author(s): Yuria Sawada, Makiko Yamashita, Eri Sawai, Marina Henmi, Aya Hirata, Chihiro Shibasaki, Hironori Fukuda, Yukihiro Mizoguchi, Kazunori Aoki
  • Organizer: 第77回日本癌学会総会
• [Presentation] The role of cancer associated fibroblasts in immune suppressive microenvironment of lung cancer (2018)
  • Author(s): Eri Sawai, Makiko Yamashita, Marina Henmi, Aya Hirata, Yuria Sawada, Chihiro Shibasaki, Yukihiro Mizoguchi, Makoto Miyazaki, Genichiro Ishii, Kazunori Aok
  • Organizer: 第77回日本癌学会総会
• [Presentation] Interferon-alpha reduces trafficking of regulatory T cells into tumor by inhibition of CCL17 expression (2017)
  • Author(s): Kazunori Aoki, Chihiro Shibasaki, Hisayoshi Hashimoto
  • Organizer: American Association of Cancer Research
  • Int'l Joint Research
• [Presentation] Effect of Imatinib mesylate to immunosuppressive microenvironment in tumor (2017)
  • Author(s): Aya Hirata, Chihiro Shibasaki, Marina Henmi, Yukihiro Mizoguchi, Kazunori Aoki.
  • Organizer: 第76回日本癌学会総会
• [Presentation] The priming of donor cells by GITR agonist antibody enhances the antitumor immunity of hematopoietic stem cell transplantation against solid cancer (2017)
  • Author(s): Marina Henmi, Yukihiro Mizoguchi, Aya Hirata, Kazunori Aoki.
  • Organizer: 第76回日本癌学会総会
• [Presentation] Mechanism of Antitumor immunity induced by intratumoral injection of GITR Ab (2017)
  • Author(s): Chihiro Shibasaki, Kenta Narumi, Marina Henmi, Kazunori Aoki.
  • Organizer: 第76回日本癌学会総会
• [Presentation] Effect of Imatinib mesylate to immunosuppressive microenvironment in tumor (2017)
  • Author(s): Aya Hirata, Chihiro Shibasaki, Marina Henmi, Yukihiro Mizoguchi, Hajime Takizawa, Kazunori Aoki
  • Organizer: 第46回日本免疫学会
• [Presentation] Intratumoral IFN-α expression reduces trafficking of Tregs into tumor by inhibition of CCL17 expression (2016)
  • Author(s): Aoki K, Shibasaki C, Hashimoto H
  • Organizer: 第45回日本免疫学会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県、宜野湾）〉
  • Year and Date: 2016-12-05
• [Presentation] Targeting FSTL1 is a new approach to treatment of pediatric cancers (2016)
  • Author(s): Henmi M, Ogiwara Y, Toyoura M, Aoki K, Kudo C
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
• [Presentation] ntratumoral IFN-α expression reduces trafficking of Tregs into tumor by inhibition of CCL17 expression in tumors (2016)
  • Author(s): Aoki K, Shibasaki C, Hashimoto H, Narumi K, Ueda R
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Development of prostate cancer-targeted adenovirus vector with peptide-displaying Ad library (2016)
  • Author(s): Nagasato M, Rin Y, Henmi M, Yamamoto Y, Aoki K
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-06