Deciphering the cholangiocarcinoma-microenvironment interactions to identify clinical biomarkers of treatment response

Abstract :

The management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging due to the unavailability of effective treatments. Immune checkpoint inhibitors are currently under investigation and addition of durvalumab to standard chemotherapy recently demonstrated a survival benefit as first-line therapy. However, these results were obtained in an unselected population, and no information is available on the tumor characteristics or circulating biomarkers which could predict the response to immunotherapy. A peculiar feature of iCCA is the dense desmoplastic stroma which surrounds cancer cells, comprised of matrix-producing myofibroblasts and different immune cells, and constituting the tumor immune microenvironment (TIME). The goal of this project is to identify therapy-specific predictive biomarkers focusing on the tumor immune microenvironment (TIME), to determine the optimal personalized treatment for iCCA patients. To reach this goal we aim: 1) to profile TIME and TIME-iCCA interactions, characterizing the miRNA-mRNA network related to the regulation of the immune network; 2) to profile longitudinally the miRNA-mRNA network and the mutational load of iCCA in liquid biopsy; 3) to analyze in vitro the mechanisms underlying iCCA-TIME interplay. We expect, in a prospective observational study, to identify potential tissue and liquid predictive biomarkers of response and/or toxicity in patients receiving first-line CT-ICI therapy for advanced iCCA. In addition, we plan to develop in vitro systems which could be helpful in predicting the response to therapy and possibly to generate new targets for treatment.