期刊
FRONTIERS IN ONCOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2019.00156
关键词
radiotherapy; immunosuppression; immune checkpoint inhibitors; PD-L1; PD-1
类别
资金
- Alexander von Humboldt Fellowship
- BMBF Innovative therapies [01GU0823]
- BMBF Kompetenzverbund Strahlenforschung [02NUK038A]
- BMWi (AiF project) [ZF4320102CS7]
- German Research Foundation DFG [SFB824/3]
- DFG [STA1520/1-1]
- Russian Foundation for Basic Research (RFBR) [19-08-00024]
- Federal Agency of Scientific Organizations in Russia
- Technische Universitat Munchen (TUM) within the DFG funding programme Open Access Publishing
- JSPS KAKENHI [JP17H04713, JP17K16420]
- Cell Science Research Foundation
- Daiichi Sankyo Foundation of Life Science
- Yasuda Medical Foundation
- Takeda Science Foundation
- Program of the network-type Joint Usage/Research Center for Radiation Disaster Medical Science of Hiroshima University
- Nagasaki University
- Fukushima Medical University
- [277386067]
Radiotherapy (RT) has been applied for decades as a treatment modality in the management of various types of cancer. Ionizing radiation induces tumor cell death, which in turn can either elicit protective anti-tumor immune responses or immunosuppression in the tumor micromilieu that contributes to local tumor recurrence. Immunosuppression is frequently accompanied by the attraction of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), M2 tumor-associated macrophages (TAMs), T regulatory cells (Tregs), N2 neutrophils, and by the release of immunosuppressive cytokines (TGF-beta, IL-10) and chemokines. Immune checkpoint pathways, particularly of the PD-1/PD-L1 axis, have been determined as key regulators of cancer immune escape. While IFN-dependent upregulation of PD-L1 has been extensively investigated, up-to-date studies indicated the importance of DNA damage signaling in the regulation of PD-L1 expression following RT. DNA damage dependent PD-L1 expression is upregulated by ATM/ATR/Chk1 kinase activities and cGAS/STING-dependent pathway, proving the role of DNA damage signaling in PD-L1 induced expression. Checkpoint blockade immunotherapies (i.e., application of anti-PD-1 and anti-PD-L1 antibodies) combined with RT were shown to significantly improve the objective response rates in therapy of various primary and metastatic malignancies. Further improvements in the therapeutic potential of RT are based on combinations of RT with other immunotherapeutic approaches including vaccines, cytokines and cytokine inducers, and an adoptive immune cell transfer (DCs, NK cells, T cells). In the current review we provide immunological rationale for a combination of RT with various immunotherapies as well as analysis of the emerging preclinical evidences for these therapies.
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