Institute of Human Genetics, Ulm University Medical Center, Ulm, Germany.
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany.
Nat Commun. 2024 Oct 3;15(1):8571. doi: 10.1038/s41467-024-52826-0.
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, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOS 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. 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 within the TME.
外周 T 细胞淋巴瘤，非特指型（PTCL-NOS）是一组预后不良的异质性恶性肿瘤。在这里，我们确定了一个亚组，PTCL-NOS，其特征是缺乏 SMARCB1 蛋白，并且更常发生在年轻患者中。人和鼠的 PTCL-NOS 表现出相似的 DNA 甲基化谱，T 细胞相关基因的高甲基化和参与髓系发育的基因的低甲基化。人类和鼠肿瘤的单细胞分析揭示了肿瘤细胞之间丰富而复杂的相互作用网络，以及免疫抑制和耗竭的肿瘤微环境（TME）。在药物筛选中，我们发现组蛋白去乙酰化酶抑制剂（HDACi）是一类有效治疗 PTCL-NOS 的药物。在体内用 pan-HDACi SAHA 治疗小鼠肿瘤会引发 TME 的重塑，促进淋巴器官的补充和耗竭表型的逆转。这些结果为进一步探索针对 TME 中的 PTCL-NOS 的 HDACi 联合治疗提供了依据。
