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

: Hutchinson, J.A.; Kronenberg, K.; Riquelme, P.; Wenzel, J.J.; Glehr, G.; Schilling, H.-L.; Zeman, F.; Evert, K.; Schmiedel, M.; Mickler, M.; Drexler, K.; Bitterer, F.; Cordero, L.; Beyer, L.; Bach, C.; Koestler, J.; Burkhardt, R.; Schlitt, H.J.; Hellwig, D.; Werner, J.M.; Spang, R.; Schmidt, B.; Geissler, E.K.; Haferkamp, S.

Volltext ()

Nature Communications 12 (2021), Art. 1439, 15 S.
ISSN: 2041-1723
Zeitschriftenaufsatz, Elektronische Publikation
Fraunhofer ITEM ()

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.