Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis

Journal of Translational Medicine

Research

Luis Kluth¹  Severine Banek¹  Felix K.-H. Chun¹  Florestan J. Koll²  Henning Reis³  Katrin Bankov³  Jens Köllermann³  Peter J. Wild⁴  Andreas Weigert⁵ 

[1] Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany;Department of Urology, University Hospital Frankfurt, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany;Frankfurt Cancer Institute (FCI), University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany;University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany;Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 60590, Frankfurt am Main, Germany;Frankfurt Cancer Institute (FCI), University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany;Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, 60590, Frankfurt am Main, Germany;Frankfurt Institute for Advanced Studies, 60438, Frankfurt am Main, Germany;Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany;

关键词: Bladder cancer;    MIBC;    TAM;    Immune cells;    Chemotherapy;    Treg;   

DOI  :  10.1186/s12967-023-03949-3

 received in 2022-12-13, accepted in 2023-02-01,  发布年份 2023

来源: Springer

【 摘 要 】

Introduction and objectiveMuscle-invasive urothelial bladder cancer (MIBC) is associated with limited response rates to systemic therapy, risk of recurrence and death. Tumor infiltrating immune cells have been associated with outcome and response to chemo-and immunotherapy in MIBC. We aimed to profile the immune cells in the tumor microenvironment (TME) to predict prognosis in MIBC and responses to adjuvant chemotherapy.MethodsWe performed multiplex immunohistochemistry (IHC) profiling and quantification of immune and stromal cells (CD3, CD4, CD8, CD163, FoxP3, PD-1, and CD45, Vimentin, αSMA, PD-L1, Pan-Cytokeratin, Ki67) in 101 patients with MIBC receiving radical cystectomy. We used uni- and multivariate survival analyses to identify cell types predicting prognosis. Samples were subdivided using K-means clustering for Treg and macrophage infiltration resulting in 3 clusters, Cluster 1: Treg high, cluster 2: macrophage high, cluster 3: Treg and macrophage low. Routine CD68 and CD163 IHC were analyzed with QuPath in an extended cohort of 141 MIBC.ResultsHigh concentrations of macrophages were associated with increased risk of death (HR 10.9, 95% CI 2.8–40.5; p < 0.001) and high concentrations of Tregs were associated with decreased risk of death (HR 0.1, 95% CI 0.01–0.7; p = 0.03) in the multivariate Cox-regression model adjusting for adjuvant chemotherapy, tumor and lymph node stage. Patients in the macrophage rich cluster (2) showed the worst OS with and without adjuvant chemotherapy. The Treg rich cluster (1) showed high levels of effector and proliferating immune cells and had the best survival. Cluster 1 and 2 both were rich in PD-1 and PD-L1 expression on tumor and immune cells.ConclusionTreg and macrophage concentrations in MIBC are independent predictors of prognosis and are important players in the TME. Standard IHC with CD163 for macrophages is feasible to predict prognosis but validation to use immune-cell infiltration, especially to predict response to systemic therapies, is required.

【 授权许可】

CC BY   
© The Author(s) 2023

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