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
外周 IFN-γ(+) 细胞毒性淋巴细胞与肝细胞癌中基于 PD-1/PD-L1 治疗反应之间的关联
英文原题：Association between peripheral IFN-γ(+) cytotoxic lymphocytes and response to PD-1/PD-L1-based therapy in hepatocellular carcinoma.
查看英文原题
Association between peripheral IFN-γ(+) cytotoxic lymphocytes and response to PD-1/PD-L1-based therapy in hepatocellular carcinoma.
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研究概要
这些发现支持外周 IFN-γ+细胞毒性淋巴细胞作为候选无创生物标志物，用于对接受 PD-1/PD-L1 为基础治疗的 HCC 患者进行分层。
研究思路结论见上方概要
背景
程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）为基础的免疫检查点治疗（ICT），无论是单独使用还是与酪氨酸激酶抑制剂（TKIs）或贝伐珠单抗联合使用，均可使一部分肝细胞癌（HCC）患者获益，而可靠的预测性生物标志物仍然有限。
方法
2024年8月至2025年7月期间，共纳入55例接受以PD-1为基础治疗的HCC患者。根据改良实体瘤疗效评价标准（mRECIST）评估客观缓解率（ORR）。通过多参数流式细胞术分析外周细胞毒性淋巴细胞亚群及效应功能。
结果
我们观察到，ICT联合TKI组的ORR高于ICT单药治疗（54.5% vs. 29.4%；n = 22 vs. n = 17），而ICT联合bevacizumab组的ORR与ICT单药治疗相当（37.5% vs. 29.4%；n = 16 vs. n = 17）。与ICT单药治疗相比，接受ICT联合TKI治疗的患者具有更高的外周CD8 ⁺细胞毒性T淋巴细胞（CTL）比例，以及升高的IFN-γ + CTL、自然杀伤（NK）细胞和自然杀伤T（NKT）细胞百分比（均P < 0.05）。在所有治疗方案中，IFN-γ + 细胞毒性淋巴细胞频率与治疗反应相关，并显示出良好的区分能力，而循环血清IFN-γ水平则不具有信息价值。
展开英文摘要原文
BACKGROUND
Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint therapy (ICT), either alone or in combination with tyrosine kinase inhibitors (TKIs) or bevacizumab, benefits a subset of patients with hepatocellular carcinoma (HCC), and reliable predictive biomarkers remain limited.
METHODS
Between August 2024 and July 2025, 55 HCC patients treated with PD-1-based therapies were included. Objective response rate (ORR) was assessed according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Peripheral cytotoxic lymphocyte subsets and effector functions were profiled by multiparameter flow cytometry.
RESULTS
We observed that the ICT plus TKI group exhibited a higher ORR than ICT monotherapy (54.5% vs. 29.4%; n = 22 vs. n = 17), whereas the ORR in the ICT plus bevacizumab group was comparable to ICT monotherapy (37.5% vs. 29.4%; n = 16 vs. n = 17). Compared with ICT monotherapy, patients receiving ICT plus TKI therapy had higher peripheral CD8 ⁺ cytotoxic T lymphocyte (CTL) proportions and elevated percentages of IFN-γ + CTLs, natural killer (NK) cells, and natural killer T (NKT) cells (all P < 0.05). Across all treatment regimens, IFN-γ + cytotoxic lymphocytes frequencies were associated with treatment response and showed good discrimination, whereas circulating serum IFN-γ levels were not informative.
CONCLUSION
These findings support peripheral IFN-γ + cytotoxic lymphocytes as a candidate noninvasive biomarker for stratifying HCC patients receiving PD-1/PD-L1-based therapy.
论文信息
- 作者
- Lu H、Fang H、Ruan M、Duang Z、Wang Y、Liu W、Wang Q、Zhou Q
- 单位
- Department of Clinical Laboratory, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.China
- 期刊
- Frontiers in immunology2026
- 原文标识
- PubMed 41766908 · DOI 10.3389/fimmu.2026.1738116
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