Development and validation of a stromal-immune signature to predict prognosis in intrahepatic cholangiocarcinoma
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Backgrounds/Aims: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC. Methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time. Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort. Conclusions: We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.
Abstract
Backgrounds/Aims: Intrahepatic cholangiocarcinoma (ICC) is a highly desmoplastic tumor with poor prognosis even after curative resection. We investigated the associations between the composition of the ICC stroma and immune cell infiltration and aimed to develop a stromal-immune signature to predict prognosis in surgically treated ICC. Methods: We recruited 359 ICC patients and performed immunohistochemistry to detect α-smooth muscle actin (α-SMA), CD3, CD4, CD8, Foxp3, CD68, and CD66b. Aniline was used to stain collagen deposition. Survival analyses were performed to detect prognostic values of these markers. Recursive partitioning for a discrete-time survival tree was applied to define a stromal-immune signature with distinct prognostic value. We delineated an integrated stromal-immune signature based on immune cell subpopulations and stromal composition to distinguish subgroups with different recurrence-free survival (RFS) and overall survival (OS) time. Results: We defined four major patterns of ICC stroma composition according to the distributions of α-SMA and collagen: dormant (α-SMAlow/collagenhigh), fibrogenic (α-SMAhigh/collagenhigh), inert (α-SMAlow/collagenlow), and fibrolytic (α-SMAhigh/collagenlow). The stroma types were characterized by distinct patterns of infiltration by immune cells. We divided patients into six classes. Class I, characterized by high CD8 expression and dormant stroma, displayed the longest RFS and OS, whereas Class VI, characterized by low CD8 expression and high CD66b expression, displayed the shortest RFS and OS. The integrated stromal-immune signature was consolidated in a validation cohort. Conclusions: We developed and validated a stromal-immune signature to predict prognosis in surgically treated ICC. These findings provide new insights into the stromal-immune response to ICC.
참고문헌 (40)
- Banales JM, "Expert consensus document : cholangiocarcinoma : current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma(ENS-CCA)", Nat Rev Gastroenterol Hepatol, 13, pp.261~280 (2016)
- Mavros MN, "Treatment and prognosis for patients with intrahepatic cholangiocarcinoma : systematic review and meta-analysis", JAMA Surg, 149, pp.565~574 (2014)
- Sirica AE, "Intrahepatic cholangiocarcinoma : continuing challenges and translational advances", Hepatology, 69, pp.1803~1815 (2019)
- Tian MX, "Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy", Cancer Immunol Immunother, 68, pp.1369~1378 (2019)
- Gentles AJ, "The prognostic landscape of genes and infiltrating immune cells across human cancers", Nat Med, 21, pp.938~945 (2015)
- Fridman WH, "The immune contexture in cancer prognosis and treatment", Nat Rev Clin Oncol, 14, pp.717~734 (2017)
- Sirica AE, "Desmoplastic stroma and cholangiocarcinoma : clinical implications and therapeutic targeting", Hepatology, 59, pp.2397~2402 (2014)
- Ilyas SI, "Pathogenesis, diagnosis, and management of cholangiocarcinoma", Gastroenterology, 145, pp.1215~1229 (2013)
- Mahajan UM, "Immune cell and stromal signature associated with progression-free survival of patients with resected pancreatic ductal adenocarcinoma", Gastroenterology, 155, pp.1625~1639 (2018)
- Zhou Z, "Tumor-associated neutrophils and macrophages interaction contributes to intrahepatic cholangiocarcinoma progression by activating STAT3", J Immunother Cancer, 9, pp.e001946~ (2021)
- Wittekind C, "Pitfalls in the classification of liver tumors", Pathologe, 27, pp.289~293 (2006)
- Amin MB, "AJCC Cancer Staging Manual" (2017), Springer
- Zhou ZJ, "Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma", Int J Cancer, 132, pp.1080~1089 (2013)
- Zhou SL, "CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils", Carcinogenesis, 35, pp.597~605 (2014)
- Camp RL, "X-tile : a new bio-informatics tool for biomarker assessment and outcome-based cutpoint optimization", Clin Cancer Res, 10, pp.7252~7259 (2004)
- Grivennikov SI, "Immunity, inflammation, and cancer", Cell, 140, pp.883~899 (2010)
- Fridman WH, "The immune contexture in human tumours : impact on clinical outcome", Nat Rev Cancer, 12, pp.298~306 (2012)
- Biffi G, "Diversity and biology of cancer-associated fibroblasts", Physiol Rev, 101, pp.147~176 (2021)
- Özdemir BC, "Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival", Cancer Cell, 25, pp.719~734 (2014)
- Okabe H, "Hepatic stellate cells may relate to progression of intrahepatic cholangiocarcinoma", Ann Surg Oncol, 16, pp.2555~2564 (2009)
- Chuaysri C, "Alpha-smooth muscle actin-positive fibroblasts promote biliary cell proliferation and correlate with poor survival in cholangiocarcinoma", Oncol Rep, 21, pp.957~969 (2009)
- Yamauchi M, "The fibrotic tumor stroma", J Clin Invest, 128, pp.16~25 (2018)
- Bhattacharjee S, "Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts", J Clin Invest, 131, pp.e146987~ (2021)
- Jaillon S, "Neutrophil diversity and plasticity in tumour progression and therapy", Nat Rev Cancer, 20, pp.485~503 (2020)
- Sia D, "Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes", Gastroenterology, 144, pp.829~840 (2013)
- Mhaidly R, "Role of cancer-associated fibroblast subpopulations in immune infiltration, as a new means of treatment in cancer", Immunol Rev, 302, pp.259~272 (2021)
- Hegde PS, "Top 10 challenges in cancer immunotherapy", Immunity, 52, pp.17~35 (2020)
- Costa A, "Fibroblast heterogeneity and immunosuppressive environment in human breast cancer", Cancer Cell, 33, pp.463~479 (2018)
- Gok Yavuz B, "Cancer associated fibroblasts sculpt tumour microenvironment by recruiting monocytes and inducing immunosuppressive PD-1+ TAMs", Sci Rep, 9, pp.3172~ (2019)
- Zhang R, "Cancerassociated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer", Cell Death Dis, 10, pp.273~ (2019)
- Nagarsheth N, "Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy", Nat Rev Immunol, 17, pp.559~572 (2017)
- Liu T, "Cancerassociated fibroblasts : an emerging target of anti-cancer immunotherapy", J Hematol Oncol, 12, pp.86~ (2019)
- Song M, "Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression", Hepatology, 73, pp.1717~1735 (2021)
- Binnewies M, "Understanding the tumor immune microenvironment(TIME)for effective therapy", Nat Med, 24, pp.541~550 (2018)
- Maynard A, "Therapy-induced evolution of human lung cancer revealed by single-cell RNA sequencing", Cell, 182, pp.1232~1251 (2020)
- Hyder O, "A nomogram to predict long-term survival after resection for intrahepatic cholangiocarcinoma : an Eastern and Western experience", JAMA Surg, 149, pp.432~438 (2014)
- Mao X, "Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment : new findings and future perspectives", Mol Cancer, 20, pp.131~ (2021)
- Zhang M, "Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma", J Hepatol, 73, pp.1118~1130 (2020)
- Lin Y, "Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment", Neoplasia, 21, pp.1133~1142 (2019)
- Lin Y, "Geospatial immune heterogeneity reflects the diverse tumor-immune interactions in intrahepatic cholangiocarcinoma", Cancer Discov, 12, pp.2350~2371 (2022)
