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Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion

Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctio...

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Hauptverfasser: Lan, Yan (VerfasserIn) , Moustafa, Mahmoud (VerfasserIn) , Knoll, Maximilian (VerfasserIn) , Xu, Chunxiao (VerfasserIn) , Furkel, Jennifer (VerfasserIn) , Lazorchak, Adam (VerfasserIn) , Yeung, Tsz-Lun (VerfasserIn) , Hasheminasab, Sayed-Mohammad (VerfasserIn) , Jenkins, Molly H. (VerfasserIn) , Meister, Sarah (VerfasserIn) , Yu, Huakui (VerfasserIn) , Schlegel, Julian (VerfasserIn) , Marelli, Bo (VerfasserIn) , Tang, Zili (VerfasserIn) , Qin, Guozhong (VerfasserIn) , Klein, Carmen (VerfasserIn) , Qi, Jin (VerfasserIn) , Zhou, Cheng (VerfasserIn) , Locke, George (VerfasserIn) , Krunic, Damir (VerfasserIn) , Derner, Melissa G. (VerfasserIn) , Schwager, Christian (VerfasserIn) , Fontana, Rachel E. (VerfasserIn) , Kriegsmann, Katharina (VerfasserIn) , Jiang, Feng (VerfasserIn) , Rein, Katrin (VerfasserIn) , Kriegsmann, Mark (VerfasserIn) , Debus, Jürgen (VerfasserIn) , Lo, Kin-Ming (VerfasserIn) , Abdollahi, Amir (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: October 11, 2021
In: Cancer cell
Year: 2021, Jahrgang: 39, Heft: 10, Pages: 1388-1403, e1-e10
ISSN:1878-3686
DOI:10.1016/j.ccell.2021.08.008
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccell.2021.08.008
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1535610821004487
Volltext
Verfasserangaben:Yan Lan, Mahmoud Moustafa, Maximilian Knoll, Chunxiao Xu, Jennifer Furkel, Adam Lazorchak, Tsz-Lun Yeung, Sayed-Mohammad Hasheminasab, Molly H. Jenkins, Sarah Meister, Huakui Yu, Julian Schlegel, Bo Marelli, Zili Tang, Guozhong Qin, Carmen Klein, Jin Qi, Cheng Zhou, George Locke, Damir Krunic, Melissa G. Derner, Christian Schwager, Rachel E. Fontana, Katharina Kriegsmann, Feng Jiang, Katrin Rein, Mark Kriegsmann, Juergen Debus, Kin-Ming Lo, and Amir Abdollahi
Beschreibung
Zusammenfassung:Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-β trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.
Beschreibung:Gesehen am 29.01.2022
Beschreibung:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccell.2021.08.008

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