Programmed Death Ligand 1 (PD-L1)-targeted TRAIL combines PD-L1-mediated checkpoint inhibition with TRAIL-mediated apoptosis induction.
Antibodies that block PD-L1/PD-1 immune checkpoints restore the activity of functionally-impaired antitumor T cells. These antibodies show unprecedented clinical benefit in various advanced cancers, particularly in melanoma. However, only a subset of cancer patients responds to current PD-L1/PD-1-blocking strategies, highlighting the need for further advancements in PD-L1/PD-1-based immunotherapy. Here, we report on a novel approach designed to combine PD-L1 checkpoint inhibition with the tumor-selective induction of apoptosis by TNF-related Apoptosis Inducing Ligand (TRAIL). In brief, a new bi-functional fusion protein, designated anti-PD-L1:TRAIL, was constructed comprising a PD-L1-blocking antibody fragment genetically fused to the extracellular domain of the pro-apoptotic tumoricidal protein TRAIL. Treatment of PD-L1-expressing cancer cells with anti-PD-L1:TRAIL induced PD-L1-directed TRAIL-mediated cancer cell death. Treatment of T cells with anti-PD-L1:TRAIL augmented T cell activation, as evidenced by increased proliferation, secretion of IFNγ and enhanced killing of cancer cell lines and primary patient-derived cancer cells in mixed T cell/cancer cell culture experiments. Of note, elevated levels of IFNγ further upregulated PD-L1 on cancer cells and simultaneously sensitized cancer cells to TRAIL-mediated apoptosis by anti-PD-L1:TRAIL. Additionally, anti-PD-L1:TRAIL converted immunosuppressive PD-L1-expressing myeloid cells into pro-apoptotic effector cells that triggered TRAIL-mediated cancer cell death. In conclusion, combining PD-L1 checkpoint inhibition with TRAIL-mediated induction of apoptosis using anti-PD-L1:TRAIL yields promising multi-fold and mutually reinforcing anticancer activity that may be exploited to enhance the efficacy of therapeutic PD-L1/PD-1 checkpoint inhibition.
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Djoke
D
Hendriks
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Yuan
Y
He
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Iris
I
Koopmans
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Valerie R
VR
Wiersma
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Robert J
RJ
van Ginkel
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Douwe F
DF
Samplonius
University of Groningen, University Medical Center Groningen (UMCG), Department of Surgery, Laboratory for Translational Surgical Oncology , Groningen, the Netherlands.
Wijnand
W
Helfrich
University of Exeter Medical School, St Luke's Campus, Exeter, Devon, UK; University of Groningen, University Medical Center Groningen, Department of Experimental Hematology, Section Immunohematology, Cancer Research Center Groningen (CRCG), Groningen, the Netherlands.
Edwin
E
Bremer
Checkpoint inhibition; PD-L1; TRAIL; immunotherapy; melanoma