Cellular vesicles expressing PD-1-blocking scFv reinvigorate T cell immunity against cancer

Abstract

Cancer cells aberrantly express immunosuppressive checkpoint ligands and produce certain metabolites that lead to T cell exhaustion. Immune checkpoint blockade (ICB) therapy that reinvigorates exhausted T cells have achieved impressive response in clinical cancer treatment. However, the limited clinical response rate and off-tumor toxicities restrict ICB therapy. Herein, cellular vesicles displaying anti-programmed cell death-1 (PD-1) single-chain variable fragment antibody (aPD-1-scFv) were prepared to reinvigorate T cell immunity to counteract cancer. The nanovesicles displaying aPD-1-scFv (aPD-1-scFv NVs) could enhance the anti-tumor activation of T cells through PD-1 blockade. Furthermore, NVs loading the A2a adenosine receptor (A2aR) antagonist CPI-444 assisted T cells to antagonize adenosine, an immunosuppressive metabolite produced by cancer cells. Hence, CPI-444 loaded aPD-1-scFv NVs could intensively increase the density and activity of tumor infiltrating T cells, directly restraining tumor progress and metastasis.