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William J. Gradishar, MD, FACP, FASCO


Understanding Intratumor Heterogeneity in Triple-Negative Breast Cancer

By: Julia Fiederlein Cipriano
Posted: Friday, February 17, 2023

According to Zhi-Ming Shao, MD, PhD, of the Fudan University Shanghai Cancer Center, China, and colleagues, zinc finger protein 689 (ZNF689) deficiency may promote intratumor heterogeneity and resistance to immune checkpoint blockade in triple-negative breast cancer. Their findings, which were presented during the 2022 San Antonio Breast Cancer Symposium (SABCS; Abstract GS5-05), support combining long interspersed element-1 (LINE-1) inhibition and immune checkpoint blockade as a novel treatment strategy in this setting.

Using multiomics data from an institutional cohort (n = 260) and The Cancer Genome Atlas (n = 134), the investigators characterized intratumor heterogeneity at the genetic and histologic levels. Transcriptomic differences between tumors with high and low intratumor heterogeneity were compared to identify the core genes contributing to intratumor heterogeneity. The investigators used xenograft models to examine the role of key determinants in intratumor heterogeneity. Several laboratory assessments were conducted to investigate the underlying molecular mechanisms. 

High intratumor heterogeneity seemed to be associated with poor survival outcomes and immune checkpoint blockade resistance. Further analysis identified ZNF689 deficiency as a determinant of intratumor heterogeneity. According to the investigators, the ZNF689/TRIM28 complex directly bound to the promoter of LINE-1 to induce H3K9 trimethylation–mediated transcriptional silencing; ZNF689 deficiency reactivated LINE-1 retrotransposition to exacerbate genomic instability, thus promoting intratumor heterogeneity.

Antigen presentation and CD8-positive T-cell infiltration were found to be inhibited by ZNF689 deficiency–induced intratumor heterogeneity, which seemed to lead to immune checkpoint blockade resistance. The investigators noted that pharmacologic inhibition of LINE-1 retrotransposition reduced intratumor heterogeneity, augmented antitumor immunity, and eventually sensitized ZNF689-deficient tumors to immune checkpoint blockade. In clinical samples, ZNF689 expression appeared to be positively correlated with immune checkpoint blockade responsiveness and a favorable prognosis.

Disclosure: The study authors reported no conflicts of interest.

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