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.

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.

• Authors: Paul David, Malgorzata Drabczyk-Pluta, Eva Pastille, Torben Knuschke, Tanja Werner, Nadine Honke, Dominik A Megger, Ilseyar Akhmetzyanova, Namir Shaabani, Annette Eyking-Singer, Elke Cario, Olivia Kershaw, Achim D Gruber, Matthias Tenbusch, Kirsten K Dietze, Mirko Trilling, Jia Liu, Dirk Schadendorf, Hendrik Streeck, Karl S Lang, Youhua Xie, Lisa Zimmer, Barbara Sitek, Annette Paschen, Astrid M Westendorf, Ulf Dittmer, Gennadiy Zelinskyy
• Journal: PLoS pathogens (PLoS Pathog) Vol. 16 Issue 3 Pg. e1008340 (03 2020) ISSN: 1553-7374 [Electronic] United States
• PMID: 32226027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Retroviridae Infections (immunology, pathology, virology)
• T-Lymphocytes, Regulatory (immunology)
• Tumor Virus Infections (immunology, pathology, virology)