Low doses of a fusion protein comprised of LIGHT (a TNF-related cytokine) and a vascular targeting peptide (VTP) reversed tumor vessel abnormalities in mice with pancreatic tumors and enabled T cell infiltration into the tumor via LIGHT-VTP-stimulated macrophages. Combination of LIGHT-VTP with a vaccine and dual checkpoint blockade (anti-PD-1 and anti-CTLA-4) significantly reduced tumor growth, induced immune memory response, and increased survival.
The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.
Author Info: (1) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (2) Harry Perkins Institu
Author Info: (1) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (2) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (3) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (4) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (5) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (6) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia. (7) Centre for Microscopy, Characterization and Analysis, The University of Western Australia, Crawley, Western Australia, Australia. (8) Harry Perkins Institute of Medical Research, Centre for Medical Research, The University of Western Australia, Nedlands, Western Australia, Australia.
