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 Philipp Beyer, Christian Bach, Josef Koestler, Ralph Burkhardt, Hans J. Schlitt, D. Hellwig, Jens Werner, Rainer Spang, Bárbara Schmidt, Edward K. Geissler, Sebastian Haferkamp
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 (T EM cells). Pre-therapy CD4 + T EM 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 + T EM expansion. Pre-therapy CD4 + T EM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4 + T EM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4 + T EM 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.