PD1+ T-cells correlate with Nerve Fiber Density as a prognostic biomarker in patients with resected perihilar cholangiocarcinoma.

Tan, X.; Rosin, M.; Appinger, S.; Bednarsch, J.; Liu, D.; Wiltberger, G.; Garcia Vallejo, J.; Jang, S.; Czigany, Z.; Boroojerdi, S.; Gaisa, N.; Boor, P.; Buelow, R.; de Vos-Geelen, J.; Valkenburg-van Iersel, L.; Clahsen-van Groningen, M.; de Jong, E.; Groot Koerkamp, B.; Doukas, M.; Rocha, F.; Luedde, T.; Klinge, U.; Sivakumar, S.; Neumann, U.; Heij, L.

doi:10.1101/2022.01.07.475344

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bioRxiv · 10.1101/2022.01.07.475344

PD1+ T-cells correlate with Nerve Fiber Density as a prognostic biomarker in patients with resected perihilar cholangiocarcinoma.

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Abstract

Background & AimsPerihilar cholangiocarcinoma (pCCA) is a rare hepatobiliary malignancy. Nerve fiber invasion (NFI) shows cancer invading the nerve and is considered an aggressive feature. Nerve fiber density (NFD) consists of small nerve fibers without cancer invasion and is divided into high NFD (high numbers of small nerve fibers) or low NFD (low numbers of small nerve fibers). We aim to explore differences in immune cell populations and survival. MethodsWe applied multiplex immunofluorescence (mIF) on 47 pCCA surgically resected patients and investigated the immune cell composition in the tumor microenvironment (TME) of different nerve fiber phenotypes (NFI, high and low NFD). Extensive group comparison was carried out and the association with overall survival (OS) was assessed. ResultsThe NFI ROI was measured with highest CD68+ macrophage levels among 3 ROIs (NFI compared to tumor free p= 0.016 and to tumor p=0.034). Further, for NFI patients the density of co-inhibitory markers CD8+PD1+ and CD68+PD1+ were more abundant in the tumor rather than NFI ROI (p= 0.004 and p= 0.0029 respectively). Comparison between patients with NFD and NFI groups, the signals of co-expression of CD8+PD1+ as well as CD68+PD1+ were significantly higher in the high NFD group (p= 0.027 and p= 0.044, respectively). The OS for high NFD patients was 92 months median OS (95% CI:41-142), for low NFD patients 20 months ((95% CI: 4-36) and for NFI group of patients 19 months (95% CI 7-33). The OS for high NFD patients was significantly better compared to low NFD (p= 0.046) and NFI (p= 0.032). ConclusionsPD1+ T-cells correlate with high NFD as a prognostic biomarker, the biological pathway behind this needs to be investigated. Lay summaryNerve fibers play a dual role in the tumor microenvironment in pCCA. In our previous study, we showed that the presence of high numbers of small nerve fibers is associated with a better overall survival. In addition, we found that in high NFD patients PD1+ T-cells are significantly overexpressed. Therefore, we present high NFD as a promising prognostic biomarker. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/475344v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@e30fadorg.highwire.dtl.DTLVardef@11a4e4aorg.highwire.dtl.DTLVardef@a04d8org.highwire.dtl.DTLVardef@1c425db_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Tan, X., Rosin, M., Appinger, S., Bednarsch, J., Liu, D., Wiltberger, G., Garcia Vallejo, J., Jang, S., Czigany, Z., Boroojerdi, S., Gaisa, N., Boor, P., Buelow, R., de Vos-Geelen, J., Valkenburg-van Iersel, L., Clahsen-van Groningen, M., de Jong, E., Groot Koerkamp, B., Doukas, M., Rocha, F., Luedde, T., Klinge, U., Sivakumar, S., Neumann, U., Heij, L.. 2022-01-11. PD1+ T-cells correlate with Nerve Fiber Density as a prognostic biomarker in patients with resected perihilar cholangiocarcinoma.. https://doi.org/10.1101/2022.01.07.475344

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