PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma

Xiuxiang Tan, Jan Bednarsch, Mika Rosin, Simone Appinger, Dong Liu, Georg Wiltberger, Juan Garcia Vallejo, Sven Arke Lang, Zoltan Czigany, Shiva Boroojerdi, Nadine T. Gaisa, Peter Boor, Roman David Bülow, Judith De Vos-Geelen, Liselot Valkenburg-Van Iersel, Marian C. Clahsen-Van Groningen, Evelien J.M. de Jong, Bas Groot Koerkamp, Michail Doukas, Flavio G. RochaTom Luedde, Uwe Klinge, Shivan Sivakumar, Ulf Peter Neumann, Lara Rosaline Heij*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
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Background and Aims: Perihilar cholangiocarcinoma (pCCA) is a hepatobiliary malignancy, with a dismal prognosis. Nerve fiber density (NFD)—a novel prognostic biomarker—describes the density of small nerve fibers without cancer invasion and is categorized into high numbers and low numbers of small nerve fibers (high vs low NFD). NFD is different than perineural invasion (PNI), defined as nerve fiber trunks invaded by cancer cells. Here, we aim to explore differences in immune cell populations and survival between high and low NFD patients. Approach and Results: We applied multiplex immunofluorescence (mIF) on 47 pCCA patients and investigated immune cell composition in the tumor microenvironment (TME) of high and low NFD. Group comparison and oncological outcome analysis was performed. CD8+PD-1 expression was higher in the high NFD than in the low NFD group (12.24 × 10−6 vs. 1.38 × 10−6 positive cells by overall cell count, p = 0.017). High CD8+PD-1 expression was further identified as an independent predictor of overall (OS; Hazard ratio (HR) = 0.41; p = 0.031) and recurrence-free survival (RFS; HR = 0.40; p = 0.039). Correspondingly, the median OS was 83 months (95% confidence interval (CI): 18–48) in patients with high CD8+PD-1+ expression compared to 19 months (95% CI: 5–93) in patients with low CD8+PD-1+ expression (p = 0.018 log rank). Furthermore, RFS was significantly lower in patients with low CD8+PD-1+ expression (14 months (95% CI: 6–22)) compared to patients with high CD8+PD-1+ expression (83 months (95% CI: 17–149), p = 0.018 log rank). Conclusions: PD-1+ T-cells correlate with high NFD as a prognostic biomarker and predict good survival; the biological pathway needs to be investigated.

Original languageEnglish
Article number2190
Issue number9
Early online date27 Apr 2022
Publication statusPublished - 1 May 2022

Bibliographical note

Funding Information: Funding: This study was supported by the China Scholarship Council, which provided a PhD-fellowship grant to Xiuxiang Tan (number 201806210074).

Publisher Copyright: 2022 by the authors. Licensee MDPI, Basel, Switzerland.


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