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PRAME is a prominent member of the cancer testis 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 downmodulation 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 reprogramming with PRAME-targeted therapies.
Introduction
The current treatment standard of combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has achieved significant improvement in patient outcomes in diffuse large B cell lymphoma (DLBCL) over the past 15 years (1-3). However, approximately 40% of patients with DLBCL experience relapse or refractory disease. Therefore, the development of new therapeutic strategies for treatmentresistant disease is an urgent unmet clinical need in DLBCL. With the goal to translate biological discovery into clinical actionability, 2 major research foci have emerged: a) characterization of tumor cell genetics and associated cell-autonomous phenotypes and b) explication of crosstalk in the cellular ecosystem of the tumor microenvironment (TME).
Several genetic landscape studies using next-generation sequencing have contributed to a near-complete description of the most prevalent somatic gene alterations and structural genomic changes in the context of transcriptionally defined DLBCL subtypes, such as the cell-of-origin classification (4-7). However, comparatively little is known about the immune biology of DLBCL as reflected in clonal selection of specific somatic gene mutations in response to immune system pressure and the specific composition of the TME. The TME of DLBCL mainly consists of nonmalignant immune cells, such as T cells, NK cells, macrophages, and stromal cells. In recent studies, the TME has been shown to play a key role in tumor cell maintenance, immune escape, and treatment failure (8, 9). Given the importance of the activation of immune...