KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target
KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target
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DOI：
10.1182/blood.2022016765
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发表时间：
2022-09-29
期刊：
影响因子：
20.3
通讯作者：
Hermine, Olivier
中科院分区：
文献类型：
--
作者：
Cheminant, Morgane;Lhermitte, Ludovic;Hermine, Olivier
成人T细胞白血病（ATL）是一种由人类T细胞白血病病毒1型（HTLV-1）引起的淋巴样肿瘤，该病毒编码转录激活因子Tax，参与受感染T细胞的永生化。ATL分为4个亚型：阴燃型、慢性型、急性型和淋巴瘤。我们检测了自然杀伤受体（NKRs）是否在ATL中表达。在21例ATL患者中评估NKR表达（KIR2DL1/2DS1、KIR2DL2/2DL3/2DS2、KIR3DL2、NKG2A、NKG2C和NKp46），然后在71例ATL患者中评估KIR3DL2。KIR3DL2是研究中急性型与淋巴瘤型和慢性/阴燃型ATL中唯一经常表达的NKR(40人中有36人，16人中有4人，15人中有1人；P 5.001)，尽管急性型和淋巴瘤型ATL具有相似的突变谱。KIR3DL2表达与启动子去甲基化的相关性通过基于微阵列的DNA甲基化分析来确定。为探讨HTLV-1的作用，采用PrimeFlow RNA检测HTLV-1感染的ATL和CD4(+) T细胞中KIR3DL2和TAX信使RNA （mRNA）的表达水平。ATL细胞中taxmrna和KIR3DL2蛋白表达相关。HTLV-1感染可通过CD4（+）细胞触发KIR3DL2，而单独使用Tax不能诱导KIR3DL2的表达。体外，自体，抗体依赖的细胞毒性使用lacutamab，一种一流的抗KIR3DL2人源化抗体，选择性地体外杀死KIR3DL2（+）原代ATL细胞。综上所述，KIR3DL2表达与急性ATL相关。KIR3DL2的转录可能由HTLV-1感染触发，并与启动子的低甲基化相关。lacutamab靶向KIR3DL2的益处正在一项随机2期研究中进一步探讨，该研究包括ATL（在https://clinicaltrials.gov上注册为#NCT04984837）。
Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P 5.001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4(+) T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4(+) cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2(+) primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837).