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

James A Hutchinson,Florian Bitterer,Jürgen J Wenzel,Martin Schmiedel,Ralph Burkhardt,Edward K Geissler,Paloma Riquelme,Rainer Spang,Marion Mickler,Hannah-Lou Schilling,Konstantin Drexler,Dirk Hellwig,Katja Evert,Gunther Glehr,Josef Koestler,Hans J Schlitt,Katharina Kronenberg,Florian Zeman,Lukas Philipp Beyer ,Jens Werner ,Bárbara Schmidt ,Christian Bach,Laura Cordero,Sebastian Haferkamp

doi:10.1038/s41467-021-21572-y

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.

Highlights

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications
Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete[14]; these treatment-related conditions are clearly different from known autoimmune diseases[15,16]
If immune-related complications of αPD-1/αCTLA-4 therapy resulted solely from treatment-induced immunological effects[30,31], we might expect hepatitis, colitis and thyroiditis to coincide often[32] (Fig. 1b). No such associations were found in a cohort of 89 patients with metastatic melanoma treated with αPD-1/αCTLA-4 dual therapy (Fig. 1c, Supplementary Fig. 1 and Supplementary Tables 1–3)

Summary

Introduction

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. The principal limitation of αPD-1/αCTLA-4 dual therapy is the relatively high rate of immune-related complications, which commonly include colitis, hepatitis and thyroiditis, but may include pneumonitis, myocarditis and encephalitis[7,8] Such adverse events range from mild reactions to life-threatening presentations, but are clinically significant incidents that influence patient management[9,10]. Our aetiological understanding of colitis, hepatitis and thyroiditis caused by immune checkpoint blockade remains incomplete[14]; these treatment-related conditions are clearly different from known autoimmune diseases[15,16] Such adverse reactions are usually attributed to generalised dysregulation of T cells[17,18] or autoantibodies[15]. Low-level and compartmentalised reactivation of CMV can be responsible for serious acute immunopathology in humans[23,24,25]

Methods

Results

Conclusion