Lipopolysaccharide Potentiates PD-1 Targeted Therapies During Chronic Viral Infection

Abstract

Programmed cell death-1 (PD-1) targeted therapies improve exhausted T cell responses during chronic infections and cancers. However, the efficacy of PD-1 blockade as a treatment to revert CD8 T cell exhaustion declines as the chronic infection progresses. Moreover, the majority of tumors do not respond to PD-1 blockade, highlighting an important clinical limitation. Recent reports have demonstrated an association between particular microbiota and the clinical efficacy of PD-1 targeted therapies, suggesting that certain bacterial components may influence the outcome of these therapies. In this study, we interrogated synergistic effects of bacterial lipopolysaccharide (LPS), a main component of Gram-negative bacteria and a strong inducer of TLR4 signaling. Using the model of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we show that transient TLR4 stimulation with a low dose of LPS results in unprecedented potentiation of PD-1 targeted therapies via a dendritic cell intrinsic mechanism dependent on B7/CD28 costimulation. This profound synergy between PD-1 blockade and LPS was also observed in a model of advanced immune exhaustion that does not normally respond to PD-1 blockade. Taken together, our data demonstrate a potent synergy between LPS and PD-1 blockade at rejuvenating exhausted CD8 T cells during chronic infection, warranting the pre-clinical evaluation of TLR4 agonists to improve PD-1 targeted therapies.