Comprehensive immune transcriptomic analysis in bladder cancer reveals subtype specific immune gene expression patterns of prognostic relevance

// Runhan Ren 1, 2 , Kathrin Tyryshkin 3 , Charles H. Graham 1, 2 , Madhuri Koti 2, 4, 5 and D. Robert Siemens 1, 2 1 Department of Urology, Queen’s University, Kingston, ON, Canada 2 Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada 3 Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, Canada 4 Cancer Biology and Genetics Division, Queen’s Cancer Research Institute, Queen’s University, Kingston, ON, Canada 5 Department of Obstetrics and Gynecology, Queen’s University, Kingston, ON, Canada Correspondence to: D. Robert Siemens, email: siemensr@kgh.kari.net Keywords: MIBC, immune biomarkers, immunotherapy, TCGA, interferon Received: December 14, 2016      Accepted: May 21, 2017      Published: August 09, 2017 ABSTRACT Recent efforts on genome wide profiling of muscle invasive bladder cancer (MIBC) have led to its classification into distinct genomic and transcriptomic molecular subtypes that exhibit variability in prognosis. Evolving evidence from recent immunotherapy trials has demonstrated the significance of pre-existing tumour immune profiles that could guide treatment decisions. To identify immune gene expression patterns associated with the molecular subtypes, we performed a comprehensive in silico immune transcriptomic profiling, utilizing transcriptomic data from 347 MIBC cases from The Cancer Genome Atlas (TCGA). To investigate subtype-associated immune gene expression patterns, we assembled 924 immune response genes and specifically those involved in T-cell cytotoxicity and the Type I/II interferon pathways. A set of 157 ranked genes was able to distinguish the four subtypes in an unsupervised analysis in an original training cohort (n=122) and an expanded, validation cohort (n=225). The most common overrepresented pathways distinguishing the four molecular subtypes, included JAK/STAT signaling, Toll-like receptor signaling, interleukin signaling, and T-cell activation. Some of the most enriched biological processes were responses to IFN-γ, antigen processing and presentation, cytokine mediated signaling, hemopoeisis, cell proliferation and cellular defense response in the TCGA cluster IV. Our novel findings provide further insights into the association between genomic subtypes and immune activation in MIBC and may open novel opportunities for their exploitation towards precise treatment with immunotherapy.