Microbial LPS enhances PD-1 therapy during chronic LCMV infection

Abstract

Abstract CD8 T cells are critical for controlling intracellular pathogens, but during chronic viral infection, these cells become exhausted and unable to control virus. Programmed cell death-1 (PD-1) blockade therapy partially improves exhausted CD8 T cells during chronic viral infections. However, its limited efficacy in models of chronic infection has precluded its licensure to treat chronic infection. Interestingly, prior studies show that certain microbiota can improve PD-1 therapy, but the specific microbial components that mediate this positive effect remain unknown. In this study, we interrogated whether microbial LPS could enhance PD-1 therapy during chronic viral infection. Using the model of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we show that sublethal doses of LPS followed by PD-1 therapy results in synergistic improvement of virus-specific CD8 T cells in blood and tissues (~10-fold greater compared to PD-1 therapy alone). We show that the improvement of PD-1 therapy by LPS is dependent on reinforced B7/CD28 costimulation and is mediated by a dendritic cell intrinsic mechanism. Although LPS has safety concerns, prior studies show that low LPS doses (≤4 ng/kg) are well-tolerated in humans, demonstrating that there is a threshold of natural resistance to this microbial product. Altogether, our data suggest an unexpected role for LPS/TLR4 signaling in modulating response to PD-1 therapy. Our findings may be important for improving immune checkpoint therapy against chronic infections and for understanding how microbial products modulate responses to therapy.