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

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Abstract

Background: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer. Objective: To determine if TCR repertoire is more clonal in tumors than in benign inflammation. Methods: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at −80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. Results: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC−) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC− specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC− specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17% of the total tumor infiltrating lymphocyte pool, in contrast to 2% among UC− specimens. Conclusions: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance.

Original languageEnglish (US)
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
StatePublished - Jan 1 2019

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T-Cell Antigen Receptor
Urinary Bladder Neoplasms
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Urinary Bladder
Clone Cells
Antigen Receptors, T-Cell, alpha-beta
High-Throughput Nucleotide Sequencing
Neoplasm Antigens
Biotechnology
Neoplasms
Inflammation
Carcinoma
DNA
Population

Keywords

  • Immunotherapy
  • T-cell receptor
  • Urinary bladder neoplasm

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

@article{7a34ef28b4414e6797eda75d6ecdf6ba,
title = "Human urothelial bladder cancer generates a clonal immune response: The results of T-cell receptor sequencing",
abstract = "Background: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer. Objective: To determine if TCR repertoire is more clonal in tumors than in benign inflammation. Methods: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at −80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. Results: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC−) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC− specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC− specimens was 2{\%} and 12{\%}, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17{\%} of the total tumor infiltrating lymphocyte pool, in contrast to 2{\%} among UC− specimens. Conclusions: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance.",
keywords = "Immunotherapy, T-cell receptor, Urinary bladder neoplasm",
author = "Sankin, {Alexander I.} and Damini Chand and Schoenberg, {Mark P.} and Xingxing Zang",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.urolonc.2019.04.011",
language = "English (US)",
journal = "Urologic Oncology: Seminars and Original Investigations",
issn = "1078-1439",
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TY - JOUR

T1 - Human urothelial bladder cancer generates a clonal immune response

T2 - The results of T-cell receptor sequencing

AU - Sankin, Alexander I.

AU - Chand, Damini

AU - Schoenberg, Mark P.

AU - Zang, Xingxing

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer. Objective: To determine if TCR repertoire is more clonal in tumors than in benign inflammation. Methods: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at −80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. Results: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC−) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC− specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC− specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17% of the total tumor infiltrating lymphocyte pool, in contrast to 2% among UC− specimens. Conclusions: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance.

AB - Background: High T-cell receptor (TCR) repertoire clonality is associated with clinical response to immune checkpoint blockade in bladder cancer. Objective: To determine if TCR repertoire is more clonal in tumors than in benign inflammation. Methods: We prospectively identified 12 patients with bladder lesions undergoing transurethral resection. Specimens were collected at time of transurethral resection and stored at −80C. DNA was extracted and high throughput DNA sequencing of the CDR3 region of the TCR beta chain using the immunoSEQ assay (Adaptive Biotechnologies) was performed. T-cell fraction, clonal dominance, and maximum frequency of TCR clone were assessed. Results: Of the 12 bladder lesions resected, 3 of 12 were cT0, 3 of 12 were cTa, 3 of 12 were cT1, and 3 of 12 were cT2 or greater. The median number of T cells in urothelial carcinoma specimens (UC+) and benign (UC−) specimens was 5,569 and 25,872, respectively. The number of unique TCRs sequenced in UC+ and UC− specimens was 3,069 and 9,680, respectively. The median tumor infiltrating lymphocyte percentage in UC+ and UC− specimens was 2% and 12%, respectively. The UC+ specimens demonstrated clonality as evidenced by identification of a specific T-cell clone being present in up to 17% of the total tumor infiltrating lymphocyte pool, in contrast to 2% among UC− specimens. Conclusions: Primary urothelial tumors contain clonally expanded T-cell populations. These data support the hypothesis that bladder tumors induce an antigen-driven immunogenic host response, in contrast to the benign inflammatory response, which does not appear to demonstrate any T-cell clonal dominance.

KW - Immunotherapy

KW - T-cell receptor

KW - Urinary bladder neoplasm

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