Simultaneous targeting of TGF-
Menée à l'aide de modèles murins de cancer mammaire, de glioblastome, de carcinome pulmonaire de Lewis et d'adénocarcinome canalaire du pancréas, cette étude met en évidence l'intérêt d'une stratégie thérapeutique consistant à utiliser les rayonnements ionisants et une protéine de fusion inhibant à la fois le TGF-bêta et le PD-L1 pour modifier le microenvironnement tumoral et lever l'échappement des cellules cancéreuses au système immunitaire
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 ? (TGF-?). We report that a bifunctional fusion protein that simultaneously inhibits TGF-? 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-? 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.
Cancer Cell 2021