Active Autophagy Is Associated with Favorable Outcome in Patients with Surgically Resected Cholangiocarcinoma

SIMPLE SUMMARY: Autophagy can exert a dual role in the context of cancer progression. However, data on the prevalence and impact of autophagy in primary cholangiocarcinoma (CCA) tissue are very limited. Active autophagy was present in a minority of the CCA patients (23.3%). We found a significantly impaired overall survival rate for patients with non-active autophagy (32.7 months) compared to CCA patients with active autophagy (68.4 months). In line with this, absence of active autophagy was an independent risk factor for overall survival. Moreover, in patients with active autophagy, pan-acetylation was significantly more prominent compared to those with non-active autophagy. Our data strengthen the role of active autophagy as a prognostically relevant marker and a potential therapeutic target in CCA patients. ABSTRACT: Data on the impact of autophagy in primary cholangiocarcinoma (CCA) remain scarce. Here, we therefore investigated the role of active autophagy and its impact on survival in CCA patients. All CCA patients who underwent surgical resection with curative intent between 08/2005 and 12/2021 at University Hospital Frankfurt were evaluated. Autophagic key proteins were studied by immunohistochemistry. iCCA processed for gene expression profiling of immune-exhaustion gene sets was used for an autophagy approach in silico. Active autophagy was present in 23.3% of the 172 CCA patients. Kaplan–Meier curves revealed median OS of 68.4 months (95% CI = 46.9–89.9 months) and 32.7 months (95% CI = 23.6–41.8 months) for active and non-active autophagy, respectively (p ≤ 0.001). In multivariate analysis, absence of active autophagy (HR = 2, 95% CI = 1.1–3.5, p = 0.015) was an independent risk factor for OS. Differential-expression profiling revealed significantly upregulated histone deacetylases (HDAC) mRNA in patients showing non-active autophagy. In line with this, pan-acetylated lysine was significantly more prominent in CCA patients with ongoing autophagy (p = 0.005). Our findings strengthen the role of active autophagy as a prognostically relevant marker and a potential therapeutic target.