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Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.
- Source :
-
Cancer Cell . Oct2021, Vol. 39 Issue 10, p1388-1388. 1p. - Publication Year :
- 2021
-
Abstract
- 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. [Display omitted] • BA synergizes with RT to overcome tumor immune evasion via TME reprogramming • Reconstitution of tumor immunosurveillance by BART induces abscopal effects • In fibrotic lungs, PD-L1+ endothelial cells and M2-like lipofibroblasts express TGF-β • BA attenuates lung fibrosis by neutralizing TGF-β in the relevant PD-L1+ compartments Lan et al. demonstrate that tumor microenvironment reprogramming and immune activation via bintrafusp alfa (BA; targeting PD-L1 and TGF-β) and radiation therapy (RT) synergize to eradicate therapy-resistant tumors. Moreover, BA ameliorates RT-induced lung fibrosis. Clinical translation of BART may overcome inherent and acquired tumor resistance while sparing normal tissue from late toxicities. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 15356108
- Volume :
- 39
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Cancer Cell
- Publication Type :
- Academic Journal
- Accession number :
- 152901953
- Full Text :
- https://doi.org/10.1016/j.ccell.2021.08.008