Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P Modest, Johann Pratschke, Igor M Sauer, Matthäus Felsenstein
{"title":"肝内胆管癌免疫微环境中的临床预后指标和靶点。","authors":"Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P Modest, Johann Pratschke, Igor M Sauer, Matthäus Felsenstein","doi":"10.1080/2162402X.2024.2406052","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.</p><p><strong>Methods: </strong>Liver tissue samples were collected during 2008-2019 from patients (<i>n</i> = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (<i>n</i> = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (<i>n</i> = 53).</p><p><strong>Results: </strong>CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+<sup>high</sup> T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells (\"hot\" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.</p><p><strong>Conclusions: </strong>These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with \"hot\" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn \"cold\" into \"hot\" TIME in ICC.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"13 1","pages":"2406052"},"PeriodicalIF":6.5000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445892/pdf/","citationCount":"0","resultStr":"{\"title\":\"Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma.\",\"authors\":\"Isis Lozzi, Alexander Arnold, Matthias Barone, Juliette Claire Johnson, Bruno V Sinn, Johannes Eschrich, Pimrapat Gebert, Ruonan Wang, Mengwen Hu, Linda Feldbrügge, Anja Schirmeier, Anja Reutzel-Selke, Thomas Malinka, Felix Krenzien, Wenzel Schöning, Dominik P Modest, Johann Pratschke, Igor M Sauer, Matthäus Felsenstein\",\"doi\":\"10.1080/2162402X.2024.2406052\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.</p><p><strong>Methods: </strong>Liver tissue samples were collected during 2008-2019 from patients (<i>n</i> = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (<i>n</i> = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (<i>n</i> = 53).</p><p><strong>Results: </strong>CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+<sup>high</sup> T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells (\\\"hot\\\" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.</p><p><strong>Conclusions: </strong>These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with \\\"hot\\\" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn \\\"cold\\\" into \\\"hot\\\" TIME in ICC.</p>\",\"PeriodicalId\":48714,\"journal\":{\"name\":\"Oncoimmunology\",\"volume\":\"13 1\",\"pages\":\"2406052\"},\"PeriodicalIF\":6.5000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445892/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Oncoimmunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/2162402X.2024.2406052\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncoimmunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/2162402X.2024.2406052","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Clinical prognosticators and targets in the immune microenvironment of intrahepatic cholangiocarcinoma.
Background: Intrahepatic cholangiocarcinoma (ICC) is a disease with poor prognosis and limited therapeutic options. We investigated the tumor immune microenvironment (TIME) to identify predictors of disease outcome and to explore targets for therapeutic modulation.
Methods: Liver tissue samples were collected during 2008-2019 from patients (n = 139) diagnosed with ICC who underwent curative intent surgery without neoadjuvant chemotherapy. Samples from the discovery cohort (n = 86) were immunohistochemically analyzed on tissue microarrays (TMAs) for the expression of CD68, CD3, CD4, CD8, Foxp3, PD-L1, STAT1, and p-STAT1 in tumor core and stroma areas. Results were digitally analyzed using QuPath software and correlated with clinicopathological characteristics. For validation of TIME-related biomarkers, we performed multiplex imaging mass cytometry (IMC) in a validation cohort (n = 53).
Results: CD68+ cells were the predominant immune cell type in the TIME of ICC. CD4+high T cell density correlated with better overall survival (OS). Prediction modeling together with validation cohort confirmed relevance of CD4+ cells, PD-L1 expression by immune cells in the stroma and N-stage on overall disease outcome. In turn, IMC analyses revealed that silent CD3+CD4+ clusters inversely impacted survival. Among annotated immune cell clusters, PD-L1 was most relevantly expressed by CD4+FoxP3+ cells. A subset of tumors with high density of immune cells ("hot" cluster) correlated with PD-L1 expression and could identify a group of candidates for immune checkpoint inhibition (ICI). Ultimately, higher levels of STAT1 expression were associated with higher lymphocyte infiltration and PD-L1 expression.
Conclusions: These results highlight the importance of CD4+ T cells in immune response against ICC. Secondly, a subset of tumors with "hot" TIME represents potential candidates for ICI, while stimulation of STAT1 pathway could be a potential target to turn "cold" into "hot" TIME in ICC.
期刊介绍：
OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy.
As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology.
The journal covers a wide range of topics, including:
-Basic and translational studies in immunology of both solid and hematological malignancies
-Inflammation, innate and acquired immune responses against cancer
-Mechanisms of cancer immunoediting and immune evasion
-Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells
-Immunological effects of conventional anticancer therapies.
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