Combination immunotherapy with anti-PD-L1 antibody and depletion of regulatory T cells during acute viral infections results in improved virus control but lethal immunopathology.

Paul David,Tanja Werner,Malgorzata Drabczyk-Pluta,Karl S Lang,Elke Cario,Annette Eyking-Singer,Lisa Zimmer,Achim D Gruber,Ulf Dittmer,Jia Liu,Namir Shaabani,Gennadiy Zelinskyy,Olivia Kershaw,Eva Pastille,Kirsten K Dietze,Nadine Honke,Dirk Schadendorf,Torben Knuschke,Matthias Tenbusch,Youhua Xie,Mirko Trilling,Hendrik Streeck,Barbara Sitek,Astrid M Westendorf,Ilseyar Akhmetzyanova,Annette Paschen,Dominik A Megger

doi:10.1371/journal.ppat.1008340

Abstract

Combination immunotherapy (CIT) is currently applied as a treatment for different cancers and is proposed as a cure strategy for chronic viral infections. Whether such therapies are efficient during an acute infection remains elusive. To address this, inhibitory receptors were blocked and regulatory T cells depleted in acutely Friend retrovirus-infected mice. CIT resulted in a dramatic expansion of cytotoxic CD4+ and CD8+ T cells and a subsequent reduction in viral loads. Despite limited viral replication, mice developed fatal immunopathology after CIT. The pathology was most severe in the gastrointestinal tract and was mediated by granzyme B producing CD4+ and CD8+ T cells. A similar post-CIT pathology during acute Influenza virus infection of mice was observed, which could be prevented by vaccination. Melanoma patients who developed immune-related adverse events under immune checkpoint CIT also presented with expanded granzyme-expressing CD4+ and CD8+ T cell populations. Our data suggest that acute infections may induce immunopathology in patients treated with CIT, and that effective measures for infection prevention should be applied.

Highlights

Cytotoxic CD8+ T cells are crucial for the control of tumor cells and acute viral infections
Combination immunotherapy (CIT) directed against checkpoint mechanisms has been approved for the therapy of cancers and is proposed for the treatment of chronic infections
We show that acute viral infections (Friend retrovirus and Influenza virus) posed a significant threat during CIT in mice

Summary

Introduction

Cytotoxic CD8+ T cells are crucial for the control of tumor cells and acute viral infections. During chronic viral infections, like HIV or HCV, these cells become dysfunctional or “exhausted” [1]. The studies of Dr Ahmed‘s group [2] demonstrated that signaling from the programmed death receptor (PD-1) expressed on LCMV specific CD8+ T cells is a central mechanism regulating the development of T cell dysfunction during chronic viral infections. Blocking the PD-1/PD-L1 interaction and/or other inhibitory receptors, like Tim-3, results in improved control of chronic infections. These studies and previous work in tumor mouse models [3,4] paved the way to develop new immunotherapies against certain human cancers, as T cell dysfunction is a hallmark of many malignant diseases [5]. The clinical success of these immunotherapies has been outstanding for some cancer entities treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, Hodgkin lymphoma and others [6]

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