Fischer A, Albert TK, Moreno N, Interlandi M, Mormann J, Glaser S, Patil P, de Faria FW, Richter M, Verma A, Balbach ST, Wagener R, Bens S, Dahlum S, Göbel C, Münter D, Inserte C, Graf M, Kremer E, Melcher V, Di Stefano G, Santi R, Chan A, Dogan A, Bush J, Hasselblatt M, Cheng S, Spetalen S, Fosså A, Hartmann W, Herbrüggen H, Robert S, Oyen F, Dugas M, Walter C, Sandmann S, Varghese J, Rossig C, Schüller U, Tzankov A, Pedersen MB, d'Amore FA, Mellgren K, Kontny U, Kancherla V, Veloza L, Missiaglia E, Fataccioli V, Gaulard P, Burkhardt B, Soehnlein O, Klapper W, de Leval L, Siebert R, and Kerl K
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOS SMARCB1- , which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS SMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOS Smarcb1- . In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOS SMARCB1- within the TME., (© 2024. The Author(s).)