Abstract 4899: Tumor T-cell receptor (TCR) diversity elucidates the immune response to genetic alterations of muscle-invasive bladder cancer

Background: Mast cells play a critical role in tumor-associated immune pathways. We aimed to determine whether the urinary mast cell mediators predict the immune response in patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) immunotherapy. Methods: Nineteen patients who have received immunotherapy due to NMIBC and 19 healthy participants were enrolled. Urine samples were collected to assay N-methylhistamine, histamine, and tryptase levels immediately before the first BCG instillation, immediately after the third and sixth instillations, and four weeks after the sixth instillation in patients with NMIBC and at a single visit in healthy participants. Cystoscopic examinations were performed on the patient with NMIBC at three-month intervals for two years. The changes in urinary markers due to BCC response, BCG instillation, and the presence of NMIBC were assessed. Results: The average age was 56.1 ± 10.5 years in patients with NMIBC. Fourteen patients had high-grade Ta tumors, and 5 had high-grade T1 tumors. While 12 patients responded, 6 presented with recurrence and 1 with progression. There was no correlation between the levels of mast cell mediators and BCG response. The N-methylhistamine and histamine levels were increased significantly with the onset of immunotherapy, and N-methylhistamine levels were significantly decreased when immunotherapy was terminated. Pre-BCG estimated marginal means of N-methylhistamine were significantly higher in patients with NMIBC than healthy participants. Conclusions: Our study is the first study to identify the changes in mast cell mediators with the onset of immunotherapy and with the presence of bladder cancer. However, these mediators were not found to predict the patients’ response to immunotherapy.

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Human urothelial bladder cancer generates a clonal immune response: The results of T-cell receptor sequencing

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2019.04.011 ◽

2019 ◽

Vol 37 (11) ◽

pp. 810.e1-810.e5

Author(s):

Alexander Sankin ◽

Damini Chand ◽

Mark Schoenberg ◽

Xingxing Zang

Keyword(s):

Immune Response ◽

Bladder Cancer ◽

T Cell ◽

T Cell Receptor ◽

Cell Receptor ◽

Urothelial Bladder Cancer ◽

Urothelial Bladder

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Intratumoral TIGIT+ CD8+ T-cell infiltration determines poor prognosis and immune evasion in patients with muscle-invasive bladder cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000978 ◽

2020 ◽

Vol 8 (2) ◽

pp. e000978

Author(s):

Zhaopei Liu ◽

Quan Zhou ◽

Zewei Wang ◽

Hongyu Zhang ◽

Han Zeng ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

T Cell ◽

Invasive Bladder Cancer ◽

Th2 Cells ◽

Cancer Center ◽

Muscle Invasive Bladder Cancer ◽

Cell Abundance ◽

Immune Contexture ◽

Muscle Invasive

BackgroundT-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT+ CD8+ T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC).Methods259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT+ CD8+ T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry.ResultsHigh infiltration of intratumoral TIGIT+ CD8+ T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT+ CD8+ cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT+ CD8+ T-cell abundance was correlated with impaired CD8+ T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT+ CD8+ T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils.ConclusionIntratumoral TIGIT+ CD8+ T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT+ CD8+ T-cell abundance correlated with dampened CD8+ T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT+ CD8+ T-cells.

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Targeting ERBB2 mutations in urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.354 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 354-354

Author(s):

Francois Audenet ◽

Sumit Isharwal ◽

Maria E. Arcila ◽

Samuel Funt ◽

Jonathan E. Rosenberg ◽

...

Keyword(s):

Bladder Cancer ◽

Urothelial Carcinoma ◽

Allele Frequency ◽

Kinase Inhibitors ◽

Hot Spot ◽

Genetic Alterations ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Stage Disease ◽

Muscle Invasive

354 Background: ERBB2 encodes human epidermal growth factor receptor 2 (HER2), a member of the EGFR family of receptor tyrosine kinases that signal through the pro-oncogenic MAP- and PI3K-kinase pathways. ERBB2 is altered by amplification and/or overexpression in various cancers, including urothelial carcinoma (UC). These alterations could confer sensitivity to ERBB2 kinase inhibitors in selected patients with UC. Methods: Patients diagnosed with UC were enrolled onto an institutional review board approved prospective sequencing protocol. Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including ERBB2. Results: Overall, 449 samples from 429 patients were sequenced from 2013 to August 2016. Genetic alterations in ERBB2 were found in 78 samples (17%). At the time of sample collection, 24 patients (31%) had non-muscle invasive bladder cancer (NMIBC), 30 patients (38%) had muscle-invasive bladder cancer (MIBC), 18 (23%) had metastatic disease and 7 (8%) had upper tract urothelial carcinoma (UTUC). Sixteen samples (21%) came from metastatic specimens. Of the observed 78 ERBB2 alterations, 20 samples had amplifications (26%) and 58 samples had mutations (74%). Seven samples (9%) had both. We identified 71 missense, 2 inframe and 1 fusion alteration, corresponding to a somatic mutation rate of 13.1%. Thirty-seven mutations (50%) were functionally characterized hot spots that are potentially actionable. Of note, the hot spot mutation S310F/Y was found in 29 samples (37%). Its mutation allele frequency varied significantly. There was a trend towards a higher mutant allele frequency of S310F/Y in higher stage disease without reaching statistical significance (Table). In our cohort, 3 patients were enrolled in clinical trials with ERBB2 kinase inhibitors based upon the presence of an ERBB2alteration. Conclusions: ERBB2is a frequent mutation at different stages of UC. In higher stage disease, clonal selection of the S310F/Y hot-spot mutation may occur and requires further study. [Table: see text]

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