PO.TB10.04 · 肿瘤生物学

肝细胞癌对阿替利珠单抗-贝伐珠单抗获得性耐药的研究：小鼠模型和人类受试者中配对肿瘤微环境分析

Investigation of acquired resistance to atezolizumab-bevacizumab in hepatocellular carcinoma: Paired tumor microenvironment analysis in a mouse model and human subjects

编号 7422 展板 6 时间 4/22 09:00–12:00 区域 Section 28 主讲 Tsung-Hao Liu, MD

分会场 Microenvironmental Determinants of Therapy Response and Resistance 2

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作者与单位 Authors & Affiliations

Tsung-Hao Liu¹, Li-Chun Lu¹, Yu-Yun Shao², Shu-Han Yang¹, Chi-Yuan Yao¹, Chia-Lang Hsu³, Ying-Chun Shen⁴, Ann-Lii A. Cheng⁵, Chih-Hung Hsu¹

¹National Taiwan University Hospital, Taipei, Taiwan,²National Taiwan University, Taipei, Taiwan,³Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan,⁴National Taiwan University Cancer Center (NTUCC), Taipei, Taiwan,⁵Professor, Dept. of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

摘要 Abstract

中文摘要

背景：免疫治疗联合方案是晚期肝细胞癌（HCC）的标准一线治疗，但大多数反应者最终会产生耐药。进展后尚无标准的二线治疗，阐明获得性耐药机制对于指导未来策略至关重要。方法：将Hep53.4小鼠HCC细胞皮下植入C57BL/6小鼠体内，并用抗程序性死亡配体1（PD-L1）单克隆抗体（mAb）（克隆6E11，5 mg/kg）和抗血管内皮生长因子（VEGF）mAb（克隆B20-4.1.1，5 mg/kg）进行治疗。在基线期、反应期和耐药期（每组n=6）采集肿瘤，使用NanoString nCounter® Pan-Cancer IO 360™、批量RNA测序（RNA-seq）和免疫组织化学（IHC）染色进行分析。对阿替利珠单抗-贝伐珠单抗治疗进展前后的配对人类肿瘤样本（n=4）进行RNAseq分析。使用CIBERSORT估算免疫细胞比例。结果：对经抗PD-L1和抗VEGF mAb治疗的小鼠Hep53.4 HCC肿瘤不同反应期——基线期、反应期和耐药期——的NanoString分析揭示了不同的肿瘤-免疫微环境（TME）变化。肿瘤浸润淋巴细胞总数和细胞毒性T细胞在反应期肿瘤中增加，但在耐药肿瘤中下降，而耗竭性和调节性T细胞则表现出相反的趋势。B细胞或树突状细胞未观察到显著变化。值得注意的是，肥大细胞在反应期肿瘤中减少，但在耐药肿瘤中显著增加。结合CIBERSORT的RNA-seq和IHC验证了小鼠肿瘤中的免疫动态，包括肥大细胞波动。配对人类肿瘤在进展时相比基线也显示出肥大细胞富集。结论：对经抗PD-L1/VEGF mAb治疗的小鼠HCC模型的TME分析表明免疫格局发生了动态变化，反映了免疫反应-耐药现象。肥大细胞在反应时减少，但在耐药时增加——这一趋势在人类样本中得到证实。有必要进一步研究肥大细胞在获得性耐药中的作用。

查看英文原文 English abstract

Background Immunotherapy combinations are the standard first-line treatment for advanced hepatocellular carcinoma (HCC), yet most responders eventually develop resistance. No standard second-line therapy exists post-progression, and elucidating mechanisms of acquired resistance is essential to guide future strategies. Methods Hep53.4 murine HCC cells were subcutaneously implanted into C57BL/6 mice and treated with anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) (clone 6E11, 5 mg/kg) and anti-vascular endothelial growth factor (VEGF) mAb (clone B20-4.1.1, 5 mg/kg). Tumors were harvested at baseline, responding, and resistant phase (n=6 per group) for analysis using NanoString nCounter® Pan-Cancer IO 360™, bulk RNA sequencing (RNA-seq), and immunohistochemistry (IHC) staining. Paired human tumor samples (n=4) at pre- and post-progression on atezolizumab-bevacizumab were analyzed with RNAseq. Immune cell fractions were estimated using CIBERSORT. Results NanoString analysis of different response phases - baseline, responding, and resistant phase of murine Hep53.4 HCC tumors treated with anti-PD-L1 and anti-VEGF mAb revealed distinct tumor-immune microenvironment (TME) changes. Total tumor-infiltrating lymphocytes and cytotoxic T cells increased in responding tumors but declined in resistant ones, whereas exhausted and regulatory T cells showed the opposite trend. No significant changes were observed in B cells or dendritic cells. Notably, mast cells decreased in responding tumors but increased significantly in resistant ones. RNA-seq with CIBERSORT and IHC validated immune dynamics, including mast cell fluctuations, in murine tumors. Paired human tumors also showed mast cell enrichment at progression versus baseline. Conclusion TME profiling of a murine HCC model treated with anti-PD-L1/VEGF mAbs demonstrated a dynamic shift in immune contexture, mirroring the immune response-resistance phenomenon. Mast cells decreased in response but increased upon resistance-a trend confirmed in human samples. Further investigation of the role of mast cells in acquired resistance is warranted.

利益披露 Disclosure

T. Liu, None.. S. Yang, None.. C. Yao, None.

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