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Gadolinium-Based Nanoparticles Combined With Checkpoint Blockade Amplify Radiation-Induced Abscopal Effect And Cancer Immunotherapy

Authors :
Huijuan Song
Ningning He
Chang Xu
Yan Wang
Liqing Du
Yang Liu
Qin Wang
Kaihua Ji
Jinhan Wang
Manman Zhang
Yeqing Gu
Yumin Zhang
Weiwei Wang
Olivier Tillement
Li Feng
Qiang Liu
Publication Year :
2021
Publisher :
Research Square Platform LLC, 2021.

Abstract

Both immunotherapy checkpoint blocking and radiotherapy used alone in solid tumors show limited anticancer effect, due to the insufficient T cells infiltration and rarely elicited systemic immune responses. Methods: AGuIX has recently been developed for magnetic resonance imaging-guided radiotherapy and proven to act as an efficient radiosensitizer. In order to further improve the efficiency of tumor treatment, a unique synergistic strategy based on Gadolinium-based nanoparticles-AGuIX mediated radiotherapy and immunotherapy checkpoint blocking was developed for B16 tumor therapy in the present study. Clone formation, cell apoptosis and immunofluorescence were performed to detect the radiosensitization effect of AGuIX nanoparticles. The therapeutic effect was validated in both abscopal and metastasis tumor models, and analyzed the synergistic mechanism in vivo. Results: AGuIX as a radiosensitizer exacerbated radiation-induced DNA damage, cell cycle arrest and apoptosis on B16 cells. More importantly, it could efficiently induce the immunogenic cell death (ICD) of irradiated B16 tumor cells, and consequently triggered the maturation of dendritic cells (DCs) and activated systemic T-cell responses. Combining AGuIX-mediated radiotherapy with programmed cell death protein 1 (PD1) blocking demonstrated excellent synergistic therapeutic effects in both abscopal and metastasis tumor models by a significant increase in the infiltration of effector CD8+ T cells and effectively alleviating the immunosuppressive microenvironment, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in tumors.Conclusion: Our findings indicate that this combination therapy provided a new and powerful immunotherapy model to achieve durable anti-tumor responses, which is likely to be a promising comprehensive treatment strategy for cancer treatment.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........f72966055c4a608f694f1fcfa454ab64
Full Text :
https://doi.org/10.21203/rs.3.rs-1165183/v1