TLR4 signaling improves PD-1 blockade therapy during chronic viral infection

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.

Pembrolizumab in Combination with the Oncolytic Virus Pelareorep and Chemotherapy in Patients with Advanced Pancreatic Adenocarcinoma: A Phase Ib Study

“…Interestingly, expression of TICAM2 (a TLR4 pathway adaptor protein, reviewed in ref. 45) was increased after pembrolizumab administration in patients who derived benefit on-study, which provides new insights into the potential cross-talk between the TLR4 and PD-1/PD-L1 pathways in viral infections (46).…”

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

“…Fourth, protein kinase C epsilon (PRKCE) is overexpressed in most solid tumors and plays critical roles in different cancer-associated pathways, including toll-like receptor 4 (TLR-4) signaling that plays a role in the induction of both innate and adaptive immunity [78]. TLR-4 signaling was recently shown to improve anti-PD-1 therapy during chronic viral infection [79]. Enzastaurin, a protein kinase C inhibitor, thus could be used to enhance anti-PD-1 therapy in melanoma.…”

Interrogating Adaptive Immunity Using LCMV

“…PD-1-based immunotherapy for the treatment of chronic infection was first shown in the chronic LCMV Cl-13 model (Barber et al, 2006), and was then shown to also be effective in the SIV model in macaques (Velu et al, 2009). Many studies on immune regulation have utilized the LCMV system (Bhattacharyya et al, 2017b;Bhattacharyya & Penaloza-MacMaster, 2017, 2018Im et al, 2016;Kamphorst et al, 2017;Penaloza-MacMaster et al, 2011;Penaloza-MacMaster, Kamphorst et al, 2014;Penaloza-MacMaster, Masopust, & Ahmed, 2009;Penaloza-MacMaster, Provine, Blass, & Barouch, 2015;Penaloza-MacMaster, Teigler et al, 2014;Vezys et al, 2011;Wang et al, 2019;West et al, 2013;West et al, 2011).…”

“…Immunotherapies, such as PD-1/PD-L1/LAG-3 blocking antibodies, can be administered intraperitoneally, every 3 days (200 μg in 500 μl), five times. This dose is typically used in many experiments because it blocks all receptors for many inhibitory pathways (Blackburn et al, 2009;Penaloza-MacMaster, Kamphorst et al, 2014;Vezys et al, 2011;Wang et al, 2019;West et al, 2013). However, if testing a novel monoclonal antibody in vivo, titration may be needed to determine the saturating dose.…”