IL-2 therapy synergizes with PD-L1 blockade to rescue exhausted CD8+ T cells during chronic viral infection (137.24)

Abstract

Abstract Blocking PD-1 signaling, by administering anti-PD-L1 or anti-PD-1 antibodies, has proven to be effective in partially restoring CD8+ T cell function during multiple chronic infection models. However since PD-L1 blockade does not completely rescue CD8+ T cell function, we have focused on finding treatments that synergize with PD-1 blockade. Our lab has previously shown that IL-2 administration can increase the frequency of LCMV-specific CD8+ T cells and decrease viral load. Using a chronic model of lymphocytic choriomeningitis virus (LCMV) we demonstrate that combined IL-2 administration and PD-L1 blockade induces massive increases in LCMV-specific CD8+ T cells and an increased ability to produce inflammatory cytokines to multiple epitopes, including subdominant epitopes, over PD-L1 blockade alone. Furthermore, combined treatment results in greater reduction of viral loads. Importantly, IL-7Rα (CD127), a marker of functional memory cells that is not seen on exhausted cells, even after anti-PD-L1 treatment, was up-regulated on a population of LCMV-specific CD8+ T cells after IL-2 or, even more drastically, after combined treatment. These results indicate that combined IL-2 and PD-1 blockade may prove a potential therapy for increasing CD8+ T cell responses and viral control in human chronic infections.