Immunosuppressive roles of fibroblasts in a local renin angiotensin system in cancer microenvironments

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16023
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Shinshu University
• Principal Investigator: Nakamura Kenta 信州大学, 医学部, 助教(特定雇用) (90804170)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: レニンアンジオテンシン / CCL5 / 抗PD-1抗体 / 悪性黒色腫

Outline of Final Research Achievements

Cancer-associated fibroblasts (CAF) that are present in the tumor environment also express angiotensin receptors, and analyses of the effects of CAF on tumor immune responses were performed. Consequently, results showed that, upon stimulation of the renin-angiotensin system, fibroblasts produced CC motif chemokine ligand 5 (CCL5), and CCL5 production was reduced upon administration of an angiotensin receptor inhibitor (ARB). In a mouse model transplanted with malignant melanoma, ARB administration resulted in a decrease in CCL5 in the blood, an increase in tumor-infiltrating T cells, and a decrease in regulatory T cells. Increases in tumor antigen-specific T-cell responses were also observed upon ARB administration. Moreover, an ARB and anti-PD-1 antibody were administered in combination, which resulted in significant tumor growth inhibition over monotherapy.

Free Research Field

皮膚科

Academic Significance and Societal Importance of the Research Achievements

今回の研究結果より、アンジオテンシン受容体阻害薬の投与で、腫瘍免疫応答を増強することができ、抗PD-1抗体との併用効果が示された。抗PD-1抗体は、様々な種類のがんで適応が拡大されており、その治療効果を増強することができれば、多くのがん症例の治療に有益な効果をもたらす可能性がある。また、アンジオテンシン受容体阻害薬は、降圧薬として保険適応があり、併用療法を行うハードルは低いと考えられる。