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

James A. Hutchinson (), Katharina Kronenberg, Paloma Riquelme, Jürgen J. Wenzel, Gunther Glehr, Hannah-Lou Schilling, Florian Zeman, Katja Evert, Martin Schmiedel, Marion Mickler, Konstantin Drexler, Florian Bitterer, Laura Cordero, Lukas Beyer, Christian Bach, Josef Koestler, Ralph Burkhardt, Hans J. Schlitt, Dirk Hellwig, Jens M. Werner, Rainer Spang, Barbara Schmidt, Edward K. Geissler and Sebastian Haferkamp
Additional contact information
James A. Hutchinson: University Hospital Regensburg
Katharina Kronenberg: University Hospital Regensburg
Paloma Riquelme: University Hospital Regensburg
Jürgen J. Wenzel: University Hospital Regensburg
Gunther Glehr: University of Regensburg
Hannah-Lou Schilling: University Hospital Regensburg
Florian Zeman: University Hospital Regensburg
Katja Evert: University Hospital Regensburg
Martin Schmiedel: University Hospital Regensburg
Marion Mickler: University Hospital Regensburg
Konstantin Drexler: University Hospital Regensburg
Florian Bitterer: University Hospital Regensburg
Laura Cordero: University Hospital Regensburg
Lukas Beyer: University Hospital Regensburg
Christian Bach: University Hospital Erlangen
Josef Koestler: University Hospital Regensburg
Ralph Burkhardt: University Hospital Regensburg
Hans J. Schlitt: University Hospital Regensburg
Dirk Hellwig: University Hospital Regensburg
Jens M. Werner: University Hospital Regensburg
Rainer Spang: University of Regensburg
Barbara Schmidt: University Hospital Regensburg
Edward K. Geissler: University Hospital Regensburg
Sebastian Haferkamp: University Hospital Regensburg

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21572-y

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DOI: 10.1038/s41467-021-21572-y

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