Journal Article

DKFZ-2021-02018

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion.

Lan, Y. ; Moustafa, M. (First author)DKFZ* ; Knoll, M. (First author)Extern* ; Xu, C. ; Furkel, J.DKFZ* ; Lazorchak, A. ; Yeung, T.-L. ; Hasheminasab, S.DKFZ* ; Jenkins, M. H. ; Meister, S.DKFZ* ; Yu, H. ; Schlegel, J.DKFZ* ; Marelli, B. ; Tang, Z.DKFZ* ; Qin, G. ; Klein, C.DKFZ* ; Qi, J. ; Zhou, C.DKFZ* ; Locke, G. ; Krunic, D.DKFZ* ; Derner, M. G. ; Schwager, C.DKFZ* ; Fontana, R. E. ; Kriegsmann, K. ; Jiang, F. ; Rein, K.DKFZ* ; Kriegsmann, M. ; Debus, J.DKFZ* ; Lo, K.-M. ; Abdollahi, A. (Last author)DKFZ*

2021
Elsevier New York, NY

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Please use a persistent id in citations: doi:10.1016/j.ccell.2021.08.008

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.

Keyword(s): PD-L1 ; TGF-β ; abscopal effect ; compartmental targeting ; immune evasion ; immune therapy ; lung fibrosis ; radiotherapy ; tumor microenvironment ; tumor vaccination

Note: #EA:E210#LA:E210# / 2021 Oct 11;39(10):1388-1403.e10

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Contributing Institute(s):

1. E210 Translationale Radioonkologie (E210)
2. DKTK HD zentral (HD01)
3. E050 KKE Strahlentherapie (E050)
4. W210 Lichtmikroskopie (W210)

Research Program(s):

1. 315 - Bildgebung und Radioonkologie (POF4-315) (POF4-315)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 25 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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