Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis

Language
en
Document Type
Article
Issue Date
2023-03-28
First published
2021-03-04
Issue Year
2021
Authors
Hutchinson, James A.
Kronenberg, Katharina
Riquelme, Paloma
Wenzel, Jürgen J.
Glehr, Gunther
Schilling, Hannah-Lou
Zeman, Florian
Evert, Katja
Schmiedel, Martin
Mickler, Marion
Editor
Publisher
Nature Publishing Group UK
Abstract

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.

Journal Title
Nature Communications
Volume
12
Issue
1
Citation
Nature Communications 12 (2021): 1439. <https://www.nature.com/articles/s41467-021-21572-y>
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