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Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma
- Source :
- Journal of Clinical Investigation. May 15, 2022, Vol. 132 Issue 10
- Publication Year :
- 2022
-
Abstract
- 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.<br />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) [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 132
- Issue :
- 10
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.704807469
- Full Text :
- https://doi.org/10.1172/JCI145343