Endogenous Retrovirus Expression, Chromatin Abnormalities, and Response to Immune Checkpoint Blockade in Clear Cell Renal Cell Cancer
Abstract
In this study, we investigate an alternative mechanism of immune activation that may be relevant in mediating immunogenicity in low mutation burden cancers such as ccRCC: re-expression of endogenous retroviruses (ERV). Our preliminary data demonstrate that ERVs, including ERV3.2 are highly expressed in a subset of ccRCC and this expression is associated with evidence of CD8 T-cell infiltration and checkpoint gene upregulation, and is associated with response to single agent immune checkpoint blockade. Moreover, ERV expression in ccRCC and other cancers may be associated abnormalities in DNA methylation and histone methylation. Treatment of ccRCC cell lines with demethylating agents can induce expression of ERVs, including ERV3.2, and lead to induction of antiviral gene expression signature, with increased expression of key innate immune genes, in a manner dependent on viral RNA sensors such as RIG1.. Increased gene expression of elements of this antiviral response is also associated with response to ICB in ccRCC. These data support our hypothesis that ERV expression is dysregulated by epigenetic factors in a subset of ccRCC and could function as a biomarker of response to ICB. Analyses of tissue specimens are planned over the next reporting period to extend and further elaborate on these findings.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1124981
Entities
People
- Shridar Ganesan
Organizations
- Rutgers University–New Brunswick