The role of antigen-presenting CAF for tumor progression in CRC

• Project/Area Number: 21K16428
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka Metropolitan University (2022); Osaka City University (2021)
• Principal Investigator: Kasashima Hiroaki 大阪公立大学, 大学院医学研究科, 病院講師 (10899678)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 線維芽細胞 / 大腸癌 / 免疫療法 / 抗原提示細胞

Outline of Research at the Start

大腸癌の中でも癌間質の活性化を特徴とする間葉型の予後は極めて不良とされる。また、癌免疫療法に関しても、大腸癌での奏功率は低く、治療抵抗性メカニズムの解明が急務である。近年、癌間質に存在する線維芽細胞（CAF)の中でも、癌免疫を調整する可能性のある抗原提示能を持つCAF(antigen-presenting CAF; apCAF)の存在が報告されており、腫瘍抗原性調節が治療抵抗性に関与している可能性が考えられる。本研究の目的は、apCAFによる腫瘍免疫応答調節を介した癌免疫療法治療抵抗性メカニズムの解明及び大腸癌新規治療法の開発に寄与することである。

Outline of Final Research Achievements

Background: Antigen-presenting cancer-associated fibroblast (apCAF) is recently reported to be the important CAF subpopulation which regulate tumor immunity. We aim to clarify the role and effect of apCAF for tumor progression in CRCs. Method: Bioinformatic analysis and IHC analysis were performed. Flow cytometry was also performed to isolate apCAF from orthotopic tumor in mouse rectum inoculated with mouse tumor organoid. Result: The apCAF markers were highly upregulated in CAF isolated form human CRCs and metastatic liver tumor compared to normal fibroblast in colon. The prognosis of the CRC patients who have positive expression of apCAF marker was poorer than those who have negative expression of apCAF. The percentage of apCAF in orthotopic rectal tumor in mouse was approximately 26%. Discussion: In CRC, apCAF may stimulate the tumor progression. We will seek to clarify the association between apCAF and tumor immunosuppression.

Academic Significance and Societal Importance of the Research Achievements

癌免疫療法は、従来の癌治療と異なり癌の微小環境を標的とした治療法であり、国内外で多数の報告がなされているが、大腸癌の約8割の症例には癌免疫療法の有効性は不良であり、その癌免疫治療抵抗性メカニズムは未だ十分に解明されていない。この研究結果より癌免疫治療抵抗性の原因として癌微小環境、特に線維芽細胞による腫瘍免疫抑制が推察され、今後難治性癌治療において重要な意味を持つと考えられる。

Research Products

• [Int'l Joint Research] Weill Cornell Medical College/Pathology and Laboratory Medicine/Moscat & Diaz-Meco Lab(米国)
• [Journal Article] Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer (2023)
  • Author(s): Martinez-Ordonez A, Duran A, Ruiz-Martinez M, Cid-Diaz T, Zhang X, Han Q, Kinoshita H, Muta Y, Linares JF, Kasashima H, Nakanishi Y, Omar M, Nishimura S, Avila L, Yashiro M, Maeda K, Pannellini T, Pigazzi A, Inghirami G, Marchionni L, Sigal D, Diaz-Meco MT, Moscat J.
  • Journal Title: Cancer Cell Volume: 41 Issue: 2 Pages: 252-271
  • DOI: 10.1016/j.ccell.2022.11.016
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Significance of the D-Dimer Level as a Prognostic Marker for Survival and Treatment Outcomes in Patients With Stage IV Colorectal Cancer (2023)
  • Author(s): SHIBUTANI MASATSUNE、KASHIWAGI SHINICHIRO、FUKUOKA TATSUNARI、ISEKI YASUHITO、KASASHIMA HIROAKI、MAEDA KIYOSHI
  • Journal Title: In Vivo Volume: 37 Issue: 1 Pages: 440-444
  • DOI: 10.21873/invivo.13097
• [Journal Article] Prognostic significance of the Naples prognostic score in colorectal cancer patients undergoing curative resection: a propensity score matching analysis (2023)
  • Author(s): Sugimoto Atsushi、Fukuoka Tatsunari、Shibutani Masatsune、Kasashima Hiroaki、Kitayama Kishu、Ohira Masaichi、Maeda Kiyoshi
  • Journal Title: BMC Gastroenterology Volume: 23 Issue: 1 Pages: 88-88
  • DOI: 10.1186/s12876-023-02722-6
  • Peer Reviewed / Open Access
• [Journal Article] Predictive value of the Naples prognostic score on postoperative outcomes in patients with rectal cancer (2023)
  • Author(s): Sugimoto Atsushi、Fukuoka Tatsunari、Nagahara Hisashi、Shibutani Masatsune、Iseki Yasuhito、Kasashima Hiroaki、Sasaki Maho、Ohira Masaichi、Maeda Kiyoshi
  • Journal Title: Langenbeck's Archives of Surgery Volume: 408 Issue: 1 Pages: 113-113
  • DOI: 10.1007/s00423-023-02851-2
  • Peer Reviewed
• [Journal Article] The heterogeneity of cancer‐associated fibroblast subpopulations: Their origins, biomarkers, and roles in the tumor microenvironment (2022)
  • Author(s): Yamamoto Yurie、Kasashima Hiroaki、Fukui Yasuhiro、Tsujio Gen、Yashiro Masakazu、Maeda Kiyoshi
  • Journal Title: Cancer Science Volume: 114 Issue: 1 Pages: 16-24
  • DOI: 10.1111/cas.15609
• [Presentation] 大腸癌同所移植モデルと single-cell RNA sequence を用いた癌関連線維芽細胞 が及ぼす腫瘍免疫への影響の解析 (2022)
  • Author(s): 笠島裕明 福岡達成 渋谷雅常 田中浩明 八代正和 前田清
  • Organizer: 第43回癌免疫外科研究会
• [Presentation] The role of antigen-presenting CAFs for tumor-related immune microenvironment in colon cancer (2022)
  • Author(s): Hiroaki Kasashima, Kisyu Kitayama, Yuichiro Miki, Mami Yoshii, Tatsunari Fukuoka, Tatsuro Tamura, Masatsune Shibutani, Takahiro Toyokawa, Hiroaki Tanaka, Shigeru Ree, Masakazu Yashiro, Kiyoshi Maeda
  • Organizer: 第81回日本癌学会