内容紹介
Summary
The combination treatment of radiotherapy with anti-PD-1/PD-L1 antibody has been shown to significantly improve the clinical outcome of various cancers. Recent studies show that radiotherapy has multiple functions in modifying the tumor microenvironment, by inducing both immunostimulation and immunosuppression. The upregulation of PD-L1 expression in cancer cells interferes with the effector functions of interacting T cells. Preclinical studies demonstrate that radiotherapy induces PD-L1 upregulation by 4 pathways; (1)IFN-γ signaling,(2)EGFR pathway,(3)DNA damage signaling pathway, and(4)cGAS-STING pathway. All of these mechanisms are involved in the upregulation of PD-L1 expression in cancer cells via JAK/STAT pathway. Because the PD-1/PD-L1 interaction has been shown to be one of the major mechanisms of cancer immune escape, which leads to treatment failure, anti-PD-1/PD-L1 antibody may improve the efficacy of radiotherapy by enhancement of anti-tumor activity. In addition, PD-L1 expression is one of the biomarkers of good response to anti-PD-1/PD-L1 antibody. Therefore, the comprehensive understanding of the mechanism underlying PD-L1 expression in response to radiotherapy is important for the establishment of optimal combination strategy. This approach could help to provide the basis for the combined therapies and promote personalized immuno-radiotherapy, although the signaling of PD-L1 upregulation induced by radiotherapy in tumors could be intricately regulated. In this article, we review previous researches which revealed the mechanisms of PD-L1 upregulation induced by radiotherapy.
要旨
がん治療の分野において,放射線治療と抗PD-1/PD-L1抗体治療の併用が高い注目を集めている。 近年の研究により,放射線治療による腫瘍免疫環境の多様な変化が解明されるなか,放射線照射によりがん細胞のPD-L1発現が誘導されることが明らかになっている。前臨床モデルから,そのメカニズムとして① IFN-γ,② EGFR,③ DNA損傷・修復シグナル,④ cGAS-STING,以上四つの経路があげられる。また,いずれの経路でも最終的にはJAK/STAT経路を介してPD-L1発現が誘導される。PD-L1発現メカニズムの解明は,放射線治療と抗PD-1/PD-L1抗体治療の最適な併用方法の確立のために重要な課題である。本稿では,これまで明らかになっている放射線によるPD-L1発現メカニズムを概説する。
目次
The combination treatment of radiotherapy with anti-PD-1/PD-L1 antibody has been shown to significantly improve the clinical outcome of various cancers. Recent studies show that radiotherapy has multiple functions in modifying the tumor microenvironment, by inducing both immunostimulation and immunosuppression. The upregulation of PD-L1 expression in cancer cells interferes with the effector functions of interacting T cells. Preclinical studies demonstrate that radiotherapy induces PD-L1 upregulation by 4 pathways; (1)IFN-γ signaling,(2)EGFR pathway,(3)DNA damage signaling pathway, and(4)cGAS-STING pathway. All of these mechanisms are involved in the upregulation of PD-L1 expression in cancer cells via JAK/STAT pathway. Because the PD-1/PD-L1 interaction has been shown to be one of the major mechanisms of cancer immune escape, which leads to treatment failure, anti-PD-1/PD-L1 antibody may improve the efficacy of radiotherapy by enhancement of anti-tumor activity. In addition, PD-L1 expression is one of the biomarkers of good response to anti-PD-1/PD-L1 antibody. Therefore, the comprehensive understanding of the mechanism underlying PD-L1 expression in response to radiotherapy is important for the establishment of optimal combination strategy. This approach could help to provide the basis for the combined therapies and promote personalized immuno-radiotherapy, although the signaling of PD-L1 upregulation induced by radiotherapy in tumors could be intricately regulated. In this article, we review previous researches which revealed the mechanisms of PD-L1 upregulation induced by radiotherapy.
要旨
がん治療の分野において,放射線治療と抗PD-1/PD-L1抗体治療の併用が高い注目を集めている。 近年の研究により,放射線治療による腫瘍免疫環境の多様な変化が解明されるなか,放射線照射によりがん細胞のPD-L1発現が誘導されることが明らかになっている。前臨床モデルから,そのメカニズムとして① IFN-γ,② EGFR,③ DNA損傷・修復シグナル,④ cGAS-STING,以上四つの経路があげられる。また,いずれの経路でも最終的にはJAK/STAT経路を介してPD-L1発現が誘導される。PD-L1発現メカニズムの解明は,放射線治療と抗PD-1/PD-L1抗体治療の最適な併用方法の確立のために重要な課題である。本稿では,これまで明らかになっている放射線によるPD-L1発現メカニズムを概説する。