Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma.
Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma.
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DOI：
10.1172/jci145343
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发表时间：
2022-05-16
期刊：
影响因子：
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通讯作者：
Steidl C
中科院分区：
文献类型：
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作者：
Takata K;Chong LC;Ennishi D;Aoki T;Li MY;Thakur A;Healy S;Viganò E;Dao T;Kwon D;Duns G;Nielsen JS;Ben-Neriah S;Tse E;Hung SS;Boyle M;Mun SS;Bourne CM;Woolcock B;Telenius A;Kishida M;Rai S;Zhang AW;Bashashati A;Saberi S;D'Antonio G;Nelson BH;Shah SP;Hoodless PA;Melnick AM;Gascoyne RD;Connors JM;Scheinberg DA;Béguelin W;Scott DW;Steidl C
PRAME是癌症睾丸抗原蛋白家族的重要成员，其触发自体T细胞介导的免疫应答。弥漫性大B细胞淋巴瘤（DLBCL）的综合基因组分析发现，复发性和高度局灶性22 q11.22缺失，包括PRAME基因，这与不良结局相关。PRAME缺失的肿瘤表现出细胞毒性T细胞免疫逃逸，并与冷肿瘤微环境相关。此外，PRAME下调与DLBCL中的体细胞EZH 2 Y 641突变密切相关。反过来，PRC 2调节的基因在同基因PRAME-KO淋巴瘤细胞系中被抑制，并且发现PRAME作为负调节因子与EZH 2直接相互作用。用EPZ-6438抑制EZH 2消除了这些外在和内在作用，导致体内PRAME表达和微环境恢复。我们的数据突出了PRAME在淋巴瘤发生过程中的多种功能，并为表观遗传重编程与PRAME靶向治疗相结合的协同治疗提供了临床前依据。
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.