Dimethylaminomicheliolide Sensitizes Cancer Cells to Radiotherapy for Synergistic Combination with Immune Checkpoint Blockade
- 3 October 2021
- journal article
- research article
- Published by Wiley in Advanced Therapeutics
- Vol. 5 (1)
- https://doi.org/10.1002/adtp.202100160
Abstract
Radiotherapy (RT) has demonstrated synergy with immune checkpoint blockade (ICB) in preclinical models. However, its potential as an immunoadjuvant is limited by low immunogenicity at low radiation doses and immunosuppression at high radiation doses. It is hypothesized that radiosensitizers can enhance both the anticancer and immunogenic effects of low-dose radiation. Herein the authors report the antitumor immunity of combined RT and immunotherapy with dimethylaminomicheliolide (DMAMCL), a prodrug of the anti-inflammatory sesquiterpene lactone micheliolide (MCL). DMAMCL sensitized cancer cells to a single fraction of RT in vitro by inducing apoptosis and DNA double-strand breaks. DMAMCL with 5 fractions of 2 Gy focal X-ray irradiation led to significant anticancer efficacy in subcutaneous and spontaneous models of murine cancer. DMAMCL-sensitized RT upregulated programmed death-ligand 1 (PD-L1) expression in the tumors. Combination of DMAMCL-sensitized RT with anti-PD-L1 ICB significantly enhanced antitumor efficacy by increasing tumor-infiltrating CD4(+) and CD8(+) T cells and establishing immune memory.Keywords
Funding Information
- National Cancer Institute (U01‐CA198989, 1R01CA253655)
- U.S. Department of Defense (PC170934P2)
This publication has 58 references indexed in Scilit:
- Micheliolide Derivative DMAMCL Inhibits Glioma Cell Growth In Vitro and In VivoPLOS ONE, 2015
- Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in miceJCI Insight, 2014
- Ionizing-radiation induced DNA double-strand breaks: A direct and indirect lighting upRadiotherapy and Oncology, 2013
- Sesquiterpenoids Lactones: Benefits to Plants and PeopleInternational Journal of Molecular Sciences, 2013
- Modeling Prostate Cancer in Mice: Limitations and OpportunitiesJournal of Andrology, 2012
- A NADPH Oxidase–Dependent Redox Signaling Pathway Mediates the Selective Radiosensitization Effect of Parthenolide in Prostate Cancer CellsCancer Research, 2010
- Radiotherapy augments the immune response to prostate cancer in a time‐dependent mannerThe Prostate, 2008
- The radiosensitization effect of parthenolide in prostate cancer cells is mediated by nuclear factor-κB inhibition and enhanced by the presence of PTENMolecular Cancer Therapeutics, 2007
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Models of metastatic prostate cancer: a transgenic perspectiveProstate Cancer and Prostatic Diseases, 2003