Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b(+) tumor-associated-neutrophils (TAN) and CD3(+) T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. Results: Basal type BC contained a significantly higher density of CD66b(+) TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T cells and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.

Tumor Infiltrating Neutrophils Are Enriched in Basal-Type Urothelial Bladder Cancer

Mandelli, Giulio Eugenio;Missale, Francesco;Gatta, Luisa Benerini;Roca, Elisa;Bugatti, Mattia;Monti, Matilde;Belotti, Sandra;Simeone, Claudio;Calza, Stefano;Melocchi, Laura;Vermi, William
2020-01-01

Abstract

Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b(+) tumor-associated-neutrophils (TAN) and CD3(+) T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. Results: Basal type BC contained a significantly higher density of CD66b(+) TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T cells and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/529805
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