RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CML 中 KIR3DL1-HLA-Bw 状态与获得 TFR 相关：POKSTIC 试验，一项多中心观察性研究
英文原题：KIR3DL1-HLA-Bw status in CML is associated with achievement of TFR: the POKSTIC trial, a multicenter observational study.
查看英文原题
KIR3DL1-HLA-Bw status in CML is associated with achievement of TFR: the POKSTIC trial, a multicenter observational study.
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中文摘要
慢性期慢性髓性白血病（CML-CP）患者接受酪氨酸激酶抑制剂（TKI）治疗期间若获得持久的深度分子学缓解（DMR），停用TKI后实现无治疗缓解（TFR）是治疗目标，但预测TFR成功的预后因素尚不明确。
我们此前报告，杀伤细胞免疫球蛋白样受体（KIR）和HLA多态性与DMR相关。本研究调查KIR和HLA多态性与TFR的关系。
我们开展多中心协作观察研究POKSTIC（影响慢性髓性白血病患者停用酪氨酸激酶抑制剂的KIR多态性），共纳入76例CML-CP患者。中位年龄为63岁（四分位距[IQR]：49–70岁）。76例患者中，42例（56.6%；6个月时95%置信区间[CI]：47.7–66.8）停用TKI后未发生分子学复发；TFR中位随访时间为24个月（IQR：16–64个月）。KIR基因分型和等位基因分型未能识别分子学复发的风险因素；然而，单变量和多变量分析均确定KIR3DL1-HLA-Bw4（一种HLA-B等位基因）组合是分子学复发风险较高的独立因素（风险比2.206；95% CI：1.112–4.376；P=0.024）。
值得注意的是，复发风险较高患者在停用TKI时的自然杀伤（NK）细胞数量显著低于其他患者（CD16⁺/CD56⁺ NK细胞中位数分别为每升499.63个和629.17个；P=0.049）。
因此，KIR3DL1-HLA-Bw状态反映NK细胞应答，并与TFR相关。本研究已在UMIN临床试验注册平台登记，注册号为UMIN000041798。
展开英文摘要原文
Achievement of treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation in patients who show a durable deep molecular response (DMR) during TKI treatment of chronic myeloid leukemia in chronic phase (CML-CP) is a therapeutic goal; however, the prognostic factors that predict successful achievement of TFR are unclear. Previously, we reported that killer immunoglobulin-like receptor ( KIR) and HLA polymorphisms are associated with achievement of a DMR.
Here, we investigated the association between KIR and HLA polymorphisms and TFR.
We conducted the POKSTIC (POlymorphisms of Killer immunoglobulin-like receptor, which affect Stop Tyrosine kinase Inhibitor in patients with Chronic myeloid leukemia) trial, a multicenter collaborative observational study that enrolled 76 patients with CML-CP. The median age was 63 years (interquartile range [IQR], 49-70). Of 76 patients, 42 (56. 6%; 95% confidence interval [CI], 47. 7-66.
8 at 6 months) discontinued TKIs without molecular relapse; the median follow-up time for TFR was 24 months (IQR, 16-64). KIR genotyping and allele typing did not identify risk factors for molecular relapse; however, univariate and multivariate analysis identified the combination of KIR3DL1 - HLA-Bw4 (an HLA-B allele) as an independent factor for a higher risk of molecular relapse (hazard ratio, 2. 206; 95% CI, 1. 112-4. 376; P = . 024).
Notably, patients at higher risk of relapse had a significantly lower number of natural killer (NK) cells at TKI discontinuation than the other patients (CD16 + /CD56 + NK cells: median 499. 63 cells per L vs 629. 17 cells per L, respectively; P = . 049).
Thus, KIR3DL1-HLA-Bw status reflects NK cell responses and is associated with TFR. The study is registered with the UMIN Clinical Trials Registry as #UMIN000041798.
论文信息
- 作者
- Ureshino H、Ueda Y、Fujisawa S、Usuki K、Tanaka H、Okada M、Kowata S、Murai K
- 第一作者单位
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.Japan
- 通讯作者单位
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan.Japan
- 文献类型
- 临床试验
- 期刊
- Blood neoplasia2024 Mar
- 原文标识
- PubMed 40453521 · DOI 10.1016/j.bneo.2024.100001
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