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TLR4 signaling improves PD-1 blockade therapy during chronic viral infection
Yidan Wang,
Young Rock Chung,
Simon Eitzinger,
Nicole Palacio,
Shana Gregory,
Mitra Bhattacharyya,
Pablo Penaloza-MacMaster
TLR4 signaling improves PD-1 blockade therapy during chronic viral infection
Yidan Wang,
Young Rock Chung,
Simon Eitzinger,
Nicole Palacio,
Shana Gregory,
Mitra Bhattacharyya,
Pablo Penaloza-MacMaster
PLOS x
Published: February 6, 2019
https://doi.org/10.1371/journal.ppat.1007583
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Abstract
CD8 T cells are necessary for the elimination of intracellular pathogens, but during chronic viral infections, CD8 T cells become exhausted and unable to control the persistent infection. Programmed cell death-1 (PD-1) blockade therapies have been shown to improve CD8 T cell responses during chronic viral infections. These therapies have been licensed to treat cancers in humans, but they have not yet been licensed to treat chronic viral infections because limited benefit is seen in pre-clinical animal models of chronic infection. In the present study, we investigated whether TLR4 triggering could improve PD-1 therapy during a chronic viral infection. Using the model of chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we show that TLR4 triggering with sublethal doses of lipopolysaccharide (LPS) followed by PD-1 blockade results in superior improvement in circulating virus-specific CD8 T cell responses, relative to PD-1 blockade alone. Moreover, we show that the synergy between LPS and PD-1 blockade is dependent on B7 costimulation and mediated by a dendritic cell (DC) intrinsic mechanism. Systemic LPS administration may have safety concerns, motivating us to devise a safer regimen. We show that ex vivo activation of DCs with LPS, followed by adoptive DC transfer, results in a similar potentiation of PD-1 therapy without inducing wasting disease. In summary, our data demonstrate a previously unidentified role for LPS/TLR4 signaling in modulating the host response to PD-1 therapy. These findings may be important for developing novel checkpoint therapies against chronic viral infection.
Author summary
Although PD-1 therapies have revolutionized cancer treatment, these therapies have not yet been licensed to treat chronic viral infections. This is because limited benefit is seen in pre-clinical models of chronic viral infection. Interestingly, recent reports in cancer models have suggested that certain microbes can affect the efficacy of PD-1 therapies, but the specific microbial products that modulate host responses to therapy remain unknown. We utilized a model of chronic viral infection to evaluate if bacterial lipopolysaccharide (LPS), a major constituent of the microbiome, influences the efficacy of PD-1 therapy. Interestingly, we demonstrate that TLR4 triggering with low doses of LPS combined with PD-1 blockade induced a synergistic rescue of exhausted virus-specific CD8 T cell responses. Moreover, we demonstrate that adoptive transfer of LPS-activated DCs also results in similar improvement of PD-1 therapy without inducing overt immunopathology. Mechanistically, the synergy was DC-intrinsic, IFN-I independent, and B7/CD28 dependent. Taken together, our data may be important for understanding how components of the microbiome modulate the efficacy of PD-1 therapy, and may result in novel combined regimens for treating chronic viral infections.
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发表于 2019-2-9 07:23