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

PLoS Pathog. 2020 Mar 30;16(3):e1008340. doi: 10.1371/journal.ppat.1008340. eCollection 2020 Mar.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / administration & dosage*
  • B7-H1 Antigen / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • Friend murine leukemia virus / physiology
  • Humans
  • Immunotherapy / adverse effects
  • Melanoma / immunology*
  • Melanoma / pathology
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Retroviridae Infections / immunology*
  • Retroviridae Infections / pathology
  • Retroviridae Infections / virology
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Virus Infections / immunology*
  • Tumor Virus Infections / pathology
  • Tumor Virus Infections / virology

Substances

  • Antibodies
  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse

Grant support

The project was funded by two grants from the Deutsche Forschungsgemeinschaft (DFG) (https://www.dfg.de/), namely the project TRR60 (GZ, UD) grant 714/20-1 (UD) as well as receiving support from the project GRK1949 (UD, AMW). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.