Tumor associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B-cell lymphoma.

Overview

PRAME is a prominent member of the cancer germline antigen family of proteins, which triggers autologous T-cell mediated immune responses. Integrative genomic analysis in diffuse large B-cell lymphoma (DLBCL) uncovered recurrent, and highly focal deletions of 22q11.22 including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T-cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME down-modulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME KO lymphoma cell lines and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis, and provide a preclinical rationale for synergistic therapies combining epigenetic re-programming with PRAME-targeted therapies.