Blood-Epigenetic Biomarker Associations with Tumor Immunophenotype in Patients with Urothelial Carcinoma from JAVELIN Bladder 100

TL;DR

This study explores how blood-based epigenetic markers relate to immune gene activity in bladder cancer patients, suggesting their potential for predicting treatment response.

Contribution

The study introduces blood chromatin conformation markers as potential indicators of tumor immune gene expression and ICI response.

Findings

Chromatin conformation markers in blood are associated with high or low tumor immune gene expression.

These markers include genes involved in immune pathways like B-cell maturation.

Findings support using blood-based assays to assess tissue biological states.

Abstract

The JAVELIN Bladder 100 trial investigated avelumab maintenance treatment in people with advanced bladder cancer. In this exploratory analysis of data from the JAVELIN Bladder 100 trial, researchers investigated the association between chromatin conformation markers in peripheral blood specimens and tumor gene expression. Researchers identified a distinct set of chromatin conformation markers that were associated with high vs. low immune gene expression. The loci covered by these markers contained genes participating in multiple pathways that may have direct and indirect effects on immune responses. These findings support the use of blood chromatin conformation assays to query biological states in tissues.

Background/Objectives: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment. Methods: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden. Results: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation. Conclusions: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays.

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