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• W4200434853 abstract "BackgroundIntrahepatic cholangiocarcinoma (ICC) is a malignant tumor of the intrahepatic biliary ducts, with poor prognosis. The only chance of cure is by surgical resection. For patients with advanced disease, standard treatment is chemotherapy with cisplatin/gemcitabine; life expectancy is around one year. The role of immunotherapy in ICC remains unclear. Trials with immune checkpoint inhibitors (ICI) revealed disappointing results. Tumors with T cell infiltrated microenvironment (“hot” TME) show better response to ICI compared to tumors with “cold” TME (low T cell infiltration). We investigated the potential impact of mutations on the TME to identify markers of immunotherapy response or potential therapeutic approaches.MethodsThe study cohort included 86 patients without neoadjuvant chemotherapy that underwent curative intent surgical resection between 2008 and 2015 at the Dept. of Surgery, Charité –Universitätsmedizin Berlin. Next generation sequencing identified common mutations for ICC. CD3+, CD4+, CD8+, CD68+, Foxp3+, PD-L1 were evaluated by immunohistochemistry in tissue microarrays. Images were digitally analyzed by QuPath Software. Immune cell densities were obtained (cells/mm2) for different tumor compartments. PD-L1 staining ≥1% on tumor epithelium and inflammatory cells in stroma were considered positive.ResultsBy the end of the study, 81.3% (n=70) of the patients were deceased; 51.1% (n=44) had recurrence. CD4+ T cell density was predictor of better overall survival (44.5 vs. 20.2 months, p<0.01), as well as IDH (46.8 vs 27.8 months, p<0.05) and PRMB1 mutations (56.5 vs 29.5 months, p<0.01). Tumors with IDH mutations had higher densities of CD68+ (p<0.05); ARID1A, lower densities of Foxp3+, CD68+ and PD-L1 expression by inflammatory cells (p<0.05). TP53 and PRBM1 mutations (18.6% and 15.1% of patients, respectively) were associated with characteristics of “hot” TME (TP53: higher densities of CD3+, CD8+, Foxp3+; PD-L1 expression on inflammatory cells; PRMB1: higher densities of CD68+, CD3+, and CD8+ T cells).ConclusionsOur study presents new insights on the impact of mutations on the TME of ICC. Tumors with TP53 or PRMB1 mutations appear as suitable candidates for efficient ICI therapy.Legal entity responsible for the studyThe authors.FundingBerliner Krebsgesellschaft.DisclosureAll authors have declared no conflicts of interest. BackgroundIntrahepatic cholangiocarcinoma (ICC) is a malignant tumor of the intrahepatic biliary ducts, with poor prognosis. The only chance of cure is by surgical resection. For patients with advanced disease, standard treatment is chemotherapy with cisplatin/gemcitabine; life expectancy is around one year. The role of immunotherapy in ICC remains unclear. Trials with immune checkpoint inhibitors (ICI) revealed disappointing results. Tumors with T cell infiltrated microenvironment (“hot” TME) show better response to ICI compared to tumors with “cold” TME (low T cell infiltration). We investigated the potential impact of mutations on the TME to identify markers of immunotherapy response or potential therapeutic approaches. Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor of the intrahepatic biliary ducts, with poor prognosis. The only chance of cure is by surgical resection. For patients with advanced disease, standard treatment is chemotherapy with cisplatin/gemcitabine; life expectancy is around one year. The role of immunotherapy in ICC remains unclear. Trials with immune checkpoint inhibitors (ICI) revealed disappointing results. Tumors with T cell infiltrated microenvironment (“hot” TME) show better response to ICI compared to tumors with “cold” TME (low T cell infiltration). We investigated the potential impact of mutations on the TME to identify markers of immunotherapy response or potential therapeutic approaches. MethodsThe study cohort included 86 patients without neoadjuvant chemotherapy that underwent curative intent surgical resection between 2008 and 2015 at the Dept. of Surgery, Charité –Universitätsmedizin Berlin. Next generation sequencing identified common mutations for ICC. CD3+, CD4+, CD8+, CD68+, Foxp3+, PD-L1 were evaluated by immunohistochemistry in tissue microarrays. Images were digitally analyzed by QuPath Software. Immune cell densities were obtained (cells/mm2) for different tumor compartments. PD-L1 staining ≥1% on tumor epithelium and inflammatory cells in stroma were considered positive. The study cohort included 86 patients without neoadjuvant chemotherapy that underwent curative intent surgical resection between 2008 and 2015 at the Dept. of Surgery, Charité –Universitätsmedizin Berlin. Next generation sequencing identified common mutations for ICC. CD3+, CD4+, CD8+, CD68+, Foxp3+, PD-L1 were evaluated by immunohistochemistry in tissue microarrays. Images were digitally analyzed by QuPath Software. Immune cell densities were obtained (cells/mm2) for different tumor compartments. PD-L1 staining ≥1% on tumor epithelium and inflammatory cells in stroma were considered positive. ResultsBy the end of the study, 81.3% (n=70) of the patients were deceased; 51.1% (n=44) had recurrence. CD4+ T cell density was predictor of better overall survival (44.5 vs. 20.2 months, p<0.01), as well as IDH (46.8 vs 27.8 months, p<0.05) and PRMB1 mutations (56.5 vs 29.5 months, p<0.01). Tumors with IDH mutations had higher densities of CD68+ (p<0.05); ARID1A, lower densities of Foxp3+, CD68+ and PD-L1 expression by inflammatory cells (p<0.05). TP53 and PRBM1 mutations (18.6% and 15.1% of patients, respectively) were associated with characteristics of “hot” TME (TP53: higher densities of CD3+, CD8+, Foxp3+; PD-L1 expression on inflammatory cells; PRMB1: higher densities of CD68+, CD3+, and CD8+ T cells). By the end of the study, 81.3% (n=70) of the patients were deceased; 51.1% (n=44) had recurrence. CD4+ T cell density was predictor of better overall survival (44.5 vs. 20.2 months, p<0.01), as well as IDH (46.8 vs 27.8 months, p<0.05) and PRMB1 mutations (56.5 vs 29.5 months, p<0.01). Tumors with IDH mutations had higher densities of CD68+ (p<0.05); ARID1A, lower densities of Foxp3+, CD68+ and PD-L1 expression by inflammatory cells (p<0.05). TP53 and PRBM1 mutations (18.6% and 15.1% of patients, respectively) were associated with characteristics of “hot” TME (TP53: higher densities of CD3+, CD8+, Foxp3+; PD-L1 expression on inflammatory cells; PRMB1: higher densities of CD68+, CD3+, and CD8+ T cells). ConclusionsOur study presents new insights on the impact of mutations on the TME of ICC. Tumors with TP53 or PRMB1 mutations appear as suitable candidates for efficient ICI therapy. Our study presents new insights on the impact of mutations on the TME of ICC. Tumors with TP53 or PRMB1 mutations appear as suitable candidates for efficient ICI therapy." @default.
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• W4200434853 title "177P TP53 and PRBM1 mutations predict “hot” tumor microenvironment in intrahepatic cholangiocarcinoima" @default.
• W4200434853 doi "https://doi.org/10.1016/j.annonc.2021.10.197" @default.
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