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DOI: 10.1055/s-0039-3402254
Adverse effects of PD-1 targeted immunotherapy in NAFLD-triggered HCC
Publication History
Publication Date:
03 January 2020 (online)
Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) are efficiently treated others lack measurable positive effects (e.g. PDAC). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, making it a target candidate for immunotherapy. Here we investigated NAFLD-triggered HCC in the context of a metabolic syndrome and PD1-targeted immunotherapy. Using flow cytometry, single cell Seq and proteome analysis, we found a progressive increase of CD8+ effector T-cells with distinct exhaustion profiles concomitantly rising with NASH severity. We found that PD-1-targeted immunotherapy had a dismal treatment outcome at the time point of HCC initiation or at late stage HCC. We identified pre-dysfunctional PD-1+CD8+ T-cells as main drivers of disease and hepatocarcinogenesis upon PD-1-targeted immunotherapy in NASH. Similar, in a study across 6 centers in Austria and Germany, patients with NAFLD/NASH-driven HCC under PD-1-targeted immunotherapy had reduced time to progression and progression-free survival, translating to a significant worse overall survival compared to HBV, HCV or ASH-triggered HCC.
Thus, our data data indicate that PD-1-targeted immunotherapy induces adverse effects in NAFLD-driven HCC through activation of CD8+PD1+ effector T cells and NAFLD/HCC patients need to be stratified in more detail as potential non-responders with adverse effects in the context of immunotherapy.