title: Molecular Drivers of the Non-T-cell-Inflamed Tumor Microenvironment in Urothelial Bladder Cancer.
abstract: Muscle-invasive urothelial bladder cancer is a common malignancy with poor outcomes for which immune checkpoint blockade is now showing promise. Despite clinical activity of PD-1/PD-L1-targeted therapy in this disease, most patients do not benefit and resistance mechanisms remain unknown. The non-T-cell-inflamed tumor microenvironment correlates with poor prognosis and resistance to immunotherapies. In this study, we determined tumor-oncogenic pathways correlating with T-cell exclusion. We first establish in this report that T-cell-inflamed bladder tumors can be identified by immune gene expression profiling with concordance with CD8(+) T-cell infiltration. Upregulation of genes encoding immune checkpoint proteins PD-L1, IDO, FOXP3, TIM3, and LAG3 was associated with T-cell-inflamed tumors, suggesting potential for sensitivity to checkpoint blockade. β-Catenin, PPAR-γ, and FGFR3 pathways were activated in non-T-cell-inflamed tumors. No difference was seen in overall somatic mutational density between groups. The three pathways identified represent targetable potential pathways of tumor-intrinsic immunotherapy resistance. Cancer Immunol Res; 4(7); 563-8. ©2016 AACR.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Randy F
authors.initials: RF
authors.lastname: Sweis
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Stefani
authors.initials: S
authors.lastname: Spranger
authors.affiliation: Center for Research Informatics, University of Chicago, Chicago, Illinois.
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.affiliation: Department of Pathology, University of Chicago, Chicago, Illinois.
authors.forename: Gladell P
authors.initials: GP
authors.lastname: Paner
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: Department of Surgery, Section of Urology, University of Chicago, Chicago, Illinois.
authors.forename: Gary
authors.initials: G
authors.lastname: Steinberg
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois. Department of Pathology, University of Chicago, Chicago, Illinois. tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D047495:PPAR gamma / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology*; D001749:Urinary Bladder Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D047495:PPAR gamma; D061026:Programmed Cell Death 1 Receptor; D051176:beta Catenin; D051498:Receptor, Fibroblast Growth Factor, Type 3