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

• DOI: 10.1038/s41467-021-21572-y
• Publication Date: 2021-03-04T11:03:59Z
• Authors: 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; Sebastian Haferkamp
• Keywords: CD4-Positive T-Lymphocytes; ddc:610; Immunotherapy Melanoma, Predictive markers, Tumour immunology, Viral host response; Science; Q; Programmed Cell Death 1 Receptor; 610 Medizin; Cytomegalovirus; CD8-Positive T-Lymphocytes; Hepatitis A; Viral Load; Antiviral Agents; Article; 3. Good health; Cytomegalovirus Infections; Humans; Valganciclovir; CTLA-4 Antigen; ddc:610; Immune Checkpoint Inhibitors; Immunologic Memory; Melanoma

AbstractTreatment 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.