Evaluation of the effect of combination therapy with stromal response inhibitor and immune checkpoint inhibitor for colorectal cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16745
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hiroshima University
• Principal Investigator: Yuge Ryo 広島大学, 病院(医), 助教 (70794791)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 大腸癌 / 腫瘍間質 / 免疫チェックポイント阻害剤

Outline of Final Research Achievements

Phenotype classification of human colorectal cancer tissues focusing on infiltration of immune cells We performed immunostaining and phenotype classification of the immunological tumor microenvironment in nearly 200 resected human colorectal cancer specimens, more than originally planned. The relationship between these classifications and clinicopathological and prognostic factors was also analyzed. The 5-year overall survival rate showed a favorable trend in the Inflamed type. Combination effect of anti-PD-1 antibody and PDGFR inhibitor in orthotopic transplantation model of colorectal cancer We generated orthotopic transplantation mouse models of three phenotypes classified by clinical specimens. We confirmed immunohistochemically whether the created models could reproduce the microenvironment of each phenotype. Of the four groups, the combination group showed the highest anti-tumor efficacy.

Free Research Field

腫瘍間質

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害剤（ICI）の効果を増強させるための併用薬の探索は、様々な薬剤が試みられているが、有効性の高い組み合わせが見出だせていないのが現状である。また生体内でのCAFと腫瘍免疫の関連性についても報告がこれまでなかった。この理由として、腫瘍免疫微小環境を正確に再現した生体モデルが確立できていないことが挙げられる。本研究で用いたマウスモデルでの治療実験は、腫瘍免疫におけるCAFの役割の解明だけでなく、ICIの効果を増強させる新規治療標的の評価に有用であり、ICI単剤で効果がなかった大腸癌症例に対する併用療法の適応につながる可能性を見出した。