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 Rocha; Tom Luedde; Uwe Klinge; Shivan Sivakumar; Ulf Peter Neumann; Lara Rosaline Heij

doi:10.3390/cancers14092190

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 journal › Article › Academic › peer-review

Abstract

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 language	English
Article number	2190
Number of pages	15
Journal	Cancers
Volume	14
Issue number	9
DOIs	https://doi.org/10.3390/cancers14092190
Publication status	Published - 27 Apr 2022

Keywords

CLINICAL-IMPLICATIONS
INTRAHEPATIC CHOLANGIOCARCINOMA
PD-L1 EXPRESSION
SUBTYPES
cholangiocarcinoma
immune cells
immune checkpoint
liver cancer
nerve fiber density
tumor microenvironment
IMMUNE CELLS

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Tan, X., Bednarsch, J., Rosin, M., Appinger, S., Liu, D., Wiltberger, G., Garcia Vallejo, J., Lang, S. A., Czigany, Z., Boroojerdi, S., Gaisa, N. T., Boor, P., Bülow, R. D., De Vos-Geelen, J., Valkenburg-van Iersel, L., Clahsen-van Groningen, M. C., de Jong, E. J. M., Groot Koerkamp, B., Doukas, M., ... Heij, L. R. (2022). PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma. Cancers, 14(9), Article 2190. https://doi.org/10.3390/cancers14092190

@article{e1bed991d53246699deaf0bd587ea272,

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

abstract = "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.",

keywords = "CLINICAL-IMPLICATIONS, INTRAHEPATIC CHOLANGIOCARCINOMA, PD-L1 EXPRESSION, SUBTYPES, cholangiocarcinoma, immune cells, immune checkpoint, liver cancer, nerve fiber density, tumor microenvironment, IMMUNE CELLS",

author = "Xiuxiang Tan and Jan Bednarsch and Mika Rosin and Simone Appinger and Dong Liu and Georg Wiltberger and {Garcia Vallejo}, Juan and Lang, {Sven Arke} and Zoltan Czigany and Shiva Boroojerdi and Gaisa, {Nadine T} and Peter Boor and B{\"u}low, {Roman David} and {De Vos-Geelen}, Judith and {Valkenburg-van Iersel}, Liselot and {Clahsen-van Groningen}, {Marian C} and {de Jong}, {Evelien J M} and {Groot Koerkamp}, Bas and Michail Doukas and Rocha, {Flavio G} and Tom Luedde and Uwe Klinge and Shivan Sivakumar and Neumann, {Ulf Peter} and Heij, {Lara Rosaline}",

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.",

year = "2022",

month = apr,

day = "27",

doi = "10.3390/cancers14092190",

language = "English",

volume = "14",

journal = "Cancers",

issn = "2072-6694",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "9",

}

Tan, X, Bednarsch, J, Rosin, M, Appinger, S, Liu, D, Wiltberger, G, Garcia Vallejo, J, Lang, SA, Czigany, Z, Boroojerdi, S, Gaisa, NT, Boor, P, Bülow, RD, De Vos-Geelen, J , Valkenburg-van Iersel, L, Clahsen-van Groningen, MC, de Jong, EJM, Groot Koerkamp, B, Doukas, M, Rocha, FG, Luedde, T, Klinge, U, Sivakumar, S, Neumann, UP & Heij, LR 2022, 'PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma', Cancers, vol. 14, no. 9, 2190. https://doi.org/10.3390/cancers14092190

TY - JOUR

T1 - PD-1+ T-Cells Correlate with Nerve Fiber Density as a Prognostic Biomarker in Patients with Resected Perihilar Cholangiocarcinoma

AU - Tan, Xiuxiang

AU - Bednarsch, Jan

AU - Rosin, Mika

AU - Appinger, Simone

AU - Liu, Dong

AU - Wiltberger, Georg

AU - Garcia Vallejo, Juan

AU - Lang, Sven Arke

AU - Czigany, Zoltan

AU - Boroojerdi, Shiva

AU - Gaisa, Nadine T

AU - Boor, Peter

AU - Bülow, Roman David

AU - De Vos-Geelen, Judith

AU - Valkenburg-van Iersel, Liselot

AU - Clahsen-van Groningen, Marian C

AU - de Jong, Evelien J M

AU - Groot Koerkamp, Bas

AU - Doukas, Michail

AU - Rocha, Flavio G

AU - Luedde, Tom

AU - Klinge, Uwe

AU - Sivakumar, Shivan

AU - Neumann, Ulf Peter

AU - Heij, Lara Rosaline

N1 - 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.

PY - 2022/4/27

Y1 - 2022/4/27

N2 - 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.

AB - 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.

KW - CLINICAL-IMPLICATIONS

KW - INTRAHEPATIC CHOLANGIOCARCINOMA

KW - PD-L1 EXPRESSION

KW - SUBTYPES

KW - cholangiocarcinoma

KW - immune cells

KW - immune checkpoint

KW - liver cancer

KW - nerve fiber density

KW - tumor microenvironment

KW - IMMUNE CELLS

U2 - 10.3390/cancers14092190

DO - 10.3390/cancers14092190

M3 - Article

C2 - 35565318

SN - 2072-6694

VL - 14

JO - Cancers

JF - Cancers

IS - 9

M1 - 2190

ER -