AMMF’s Virtual 2021 European Cholangiocarcinoma Conference

  1. Abstract No 2

  2. Whole-transcriptome profiling of biopsies from advanced intrahepatic cholangiocarcinoma (iCCA) reveals a prognostic signature with treatment implications

Massimiliano Salati1,2,*, Colm J. O’Rourke3,*, Colin Rae4, Guido Carpino5, Maria Giuseppina Prete4, Luca Reggiani Bonetti6, Francesco Amato4, Rosie Upstill-Goddard4, Stefano Cascinu7, Andrea Spallanzani1, Fabio Gelsomino1, Francesco Caputo1, Gabriele Luppi1, Massimo Dominici1, Jesper B. Andersen3,*,#, Chiara Braconi4,*,#

* contributed equally to this work
# corresponding authors

1 Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy.
2 PhD Program, Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy.
3 Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen N, Denmark.
4 Institute of Cancer Sciences, University of Glasgow.
5 Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico,”, Rome, Italy
6 Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
7 Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy.

Background and Aims

Transcriptomics for resected iCCA are widely available. However, scarce evidence is provided for advanced iCCA with limited implications for therapeutic selection. We applied transcriptomics to a cohort of clinically-annotated advanced iCCA from patients receiving long-term benefit (Long Survivors, LS) or no-benefit (Rapid Progressor, RP) from first-line chemotherapy in order to 1) identify a prognostic signature of iCCA and 2) inform therapeutic strategies.


We used a pilot cohort of advanced iCCA patients representing the extreme spectrum of benefit from chemotherapy: RP≤6 months (N=7), LS≥23 months (N=6). Transcriptomics was performed with TempO-Seq on pretreatment liver biopsies. An RP-LS signature was developed from differentially expressed genes. This signature was evaluated in four cohorts of resected iCCA to determine the representation of the advance-stage signature in early stage disease and explore its clinical value in association to survival, signaling pathways, and immune functionality. Cell type-specific transcriptome analysis was performed by digital cytometry.


RP and LS groups were well-balanced regarding clinico-pathological features. A 504 gene differential expression signature was identified, including 310 genes categorized as LShigh (over-represented in Hedgehog signaling and mismatch repair), and 194 genes categorized as RPhigh (over-represented in NOTCH, IL-17, TNF pathways). Virtual microdissection identified differences in cell reprogramming in tumor cells and microenvironment cells (T cells, macrophages, fibroblasts). RP cases showed higher inflammatory clinico-pathological scores, and lower TIDE scores, suggesting a likelihood of response to immune checkpoint inhibitors. The RP-LS signature was found to be a stage- and genomic alteration-independent prognostic feature in resected iCCAs (n=401 cases). Further, this signature was significantly associated with microsatellite instability, decreased M2 polarization in macrophages and IFN-gamma-dominant immune subtypes.


We identified a transcriptomic-based signature capable of predicting prognosis and treatment benefits. Our study suggests that patients rapidly progressing on chemotherapy may benefit from immune checkpoint inhibitors, and that the myeloid tumor component contributes to chemoresistance and poor prognosis.

To view the poster, click here

Back to previous page