Evading immune evasion via reprograming of the tumor microenvironment by radiotherapy and simultaneous targeting of TGF-B/PD-L1

Tumor immunogenicity enhanced by radiotherapy (RT), is often counterbalanced by immune evasive mechanisms and tissue remodeling effects via upregulation of transforming growth factor-B (TGF-B) and programmed cell death-ligand 1 (PD-L1). We report that bintrafusp alfa (BA), a bifunctional fusion protein that simultaneously inhibits TGF-B and PD-L1, is a favorable combination partner for RT in eradicating multiple treatment-resistant tumor models. Beneficial effects of BA+RT (BART) are partly attributed to counterbalancing undesired RT effects and local tumor microenvironment reprograming, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Intriguingly, BA, but neither TGF-B trap nor anti-PD-L1 alone, attenuates late-stage RT-induced lung fibrosis. Single cell transcriptome show TGF-B expression is confined to PD-L1+ endothelium and M2/lipofibroblast-like cells. Hence, superior effects of BA could be attributed to its ability to trap TGF-B to relevant PD-L1+ compartments. Here, we provide rationales that BART resensitizes tumors and broadens the therapeutic window.