Dataset Information

Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

ABSTRACT: Despite the advances in cancer immunotherapy, only a fraction of patients with bladder cancer exhibit responses to checkpoint blockade, highlighting a need to better understand drug resistance and identify rational immunotherapy combinations. However, accessibility to the tumor prior and during therapy is a major limitation in understanding the immune tumor microenvironment (TME). Herein, we identified urine-derived lymphocytes (UDLs) as a readily accessible source of T cells in 32 patients with muscle invasive bladder cancer (MIBC). We observed that effector CD8⁺ and CD4⁺ cells and regulatory T cells within the urine accurately map the immune checkpoint landscape and T cell receptor repertoire of the TME. Finally, an increased UDL count, specifically high expression of PD-1 (PD-1^hi) on CD8⁺ at the time of cystectomy, was associated with a shorter recurrence-free survival. UDL analysis represents a dynamic liquid biopsy that is representative of the bladder immune TME that may be used to identify actionable immuno-oncology (IO) targets with potential prognostic value in MIBC.

SUBMITTER: Wong YNS

PROVIDER: S-EPMC6219732 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

Wong Yien Ning Sophia YNS Joshi Kroopa K Khetrapal Pramit P Ismail Mazlina M Reading James L JL Sunderland Mariana Werner MW Georgiou Andrew A Furness Andrew J S AJS Ben Aissa Assma A Ghorani Ehsan E Oakes Theres T Uddin Imran I Tan Wei Shen WS Feber Andrew A McGovern Ursula U Swanton Charles C Freeman Alex A Marafioti Teresa T Briggs Timothy P TP Kelly John D JD Powles Thomas T Peggs Karl S KS Chain Benjamin M BM Linch Mark D MD Quezada Sergio A SA

The Journal of experimental medicine 20180926 11

Despite the advances in cancer immunotherapy, only a fraction of patients with bladder cancer exhibit responses to checkpoint blockade, highlighting a need to better understand drug resistance and identify rational immunotherapy combinations. However, accessibility to the tumor prior and during therapy is a major limitation in understanding the immune tumor microenvironment (TME). Herein, we identified urine-derived lymphocytes (UDLs) as a readily accessible source of T cells in 32 patients with ...[more]

PMID: 30257862

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Project description:BackgroundStudies have shown that N6-methyl adenosine (m6A) plays an important role in cancer progression; however, the underlying mechanism of m6A modification in tumor microenvironment (TME) cell infiltration of bladder cancer remains unclear. This study aimed to investigate the role of m6A modification in TME cell infiltration of bladder cancer.MethodsThe RNA expression profile and clinical data of bladder cancer were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. We assessed the m6A modification patterns of 664 bladder cancer samples based on 20 m6A regulators through unsupervised clustering analysis and systematically linked m6A modification patterns to TME cell infiltration characteristics. Gene ontology and gene set variation analyses were conducted to analyze the underlying mechanism based on the assessment of m6A methylation regulators. Principal component analysis was used to construct the m6A score to quantify m6A modification patterns of bladder cancer.ResultsThe genetic and expression alterations in m6A regulators were highly heterogeneous between normal and bladder tissues. Three m6A modification patterns were identified. The cell infiltration characteristics were highly consistent with the three immune phenotypes, including immune rejection, immune inflammation, and immune desert. The biological functions of three m6A modification patterns were different. Cox regression analyses revealed that the m6A score was an independent signature with patient prognosis (HR = 1.198, 95% CI: 1.031-1.390). Patients with a low-m6A score were characterized by increased tumor mutation burden, PD-L1 expression, and poorer survival. Patients in the low-m6A score group also showed significant immune responses and clinical benefits in the CTLA-4 immunotherapy cohort (p =0.0069).ConclusionsThe m6A methylation modification was related to the formation of TME heterogeneity and complexity. Assessing the m6A modification pattern of individual bladder cancer will improve the understanding of TME infiltration characteristics.

Dataset Information

Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

Publications

Urine-derived lymphocytes as a non-invasive measure of the bladder tumor immune microenvironment.

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