PO.CL01.01 · 临床研究
免疫微环境驱动的11q13扩增肝细胞癌免疫治疗耐药
Immune microenvironment driven immunotherapy resistance in 11q13-amplified hepatocellular carcinoma
该海报暂无可下载的资料
AACR 官方页面
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：免疫检查点抑制剂（ICIs）为肝细胞癌（LIHC）患者提供了新的治疗机会；然而，仅有一部分患者获得有意义的获益。既往研究表明，11号染色体11q13区域（包括CCND1、FGF3、FGF4和FGF19）的共扩增与免疫治疗反应不佳及不良预后相关。尽管如此，免疫微环境是否参与11q13扩增LIHC的ICI耐药仍不明确。本研究旨在阐明LIHC中11q13扩增的基因组和免疫学相关性。
方法：使用733基因二代测序（NGS）panel分析890例LIHC患者的肿瘤样本，以表征基因组改变，包括DNA损伤修复（DDR）通路基因、肿瘤突变负荷（TMB）和瘤内异质性（ITH）。进行多重免疫荧光（mIF）以评估免疫微环境，重点关注间质和瘤内免疫细胞群。在有和无11q13扩增的患者之间进行比较分析，以确定基因组改变和免疫细胞浸润模式的差异。
结果：在890例LIHC患者中，8.9%（79/890）携带11号染色体11q13扩增。基因组分析显示，11q13扩增和非扩增患者之间在DDR通路突变、TMB或ITH方面无显著差异，提示11q13相关的免疫治疗耐药不太可能源于基因组不稳定性。相比之下，免疫微环境分析揭示了与11q13扩增相关的显著改变：扩增患者表现出间质CD8⁺ T细胞阳性率升高（P=0.04），以及瘤内CD68⁺CD163⁺ M2型肿瘤相关巨噬细胞（M2-TAMs）浸润显著升高（密度更高，P=0.03；阳性率更高，P=0.03）和CD68⁺HLA-DR⁺ M1型肿瘤相关巨噬细胞（M1-TAMs）阳性率升高（P=0.03）。这些发现表明，11q13扩增肿瘤可能具有更为复杂的免疫抑制性和炎症性微环境，可能促成ICI耐药。
结论：LIHC中11号染色体11q13扩增与独特的基因组不稳定性特征无关，但与肿瘤免疫微环境的改变强烈相关，包括CD8⁺ T细胞增多以及M1和M2型肿瘤相关巨噬细胞的富集。这些结果提示，免疫微环境失调而非基因组变异可能是11q13扩增LIHC免疫治疗耐药的基础，强调了针对这一分子定义亚组制定个体化免疫治疗策略的必要性。
查看英文原文 English abstract
Background: Immune checkpoint inhibitors (ICIs) have provided new therapeutic opportunities for patients with liver hepatocellular carcinoma (LIHC); however, only a subset of patients achieve meaningful benefit. Previous studies have suggested that co-amplification of the chromosome 11q13 region-which includes CCND1, FGF3, FGF4, and FGF19-is associated with poor immunotherapy response and unfavorable prognosis. Nonetheless, whether the immune microenvironment contributes to ICI resistance in 11q13-amplified LIHC remains unclear. This study aimed to elucidate the genomic and immunologic correlates of 11q13 amplification in LIHC.
Methods: Tumor samples from 890 LIHC patients were analyzed using a 733-gene next-generation sequencing (NGS) panel to characterize genomic alterations, including DNA damage repair (DDR) pathway genes, tumor mutation burden (TMB), and intratumor heterogeneity (ITH). Multiplex immunofluorescence (mIF) was performed to evaluate the immune microenvironment, focusing on stromal and intratumoral immune cell populations. Comparative analyses were conducted between patients with and without 11q13 amplification to determine differences in genomic alterations and immune cell infiltration patterns.
Results: Among the 890 LIHC patients, 8.9% (79/890) harbored chromosome 11q13 amplification. Genomic profiling revealed no significant differences in DDR pathway mutations, TMB, or ITH between 11q13-amplified and non-amplified patients, suggesting that 11q13-associated immunotherapy resistance is unlikely to stem from genomic instability. In contrast, immune microenvironment analysis revealed substantial alterations associated with 11q13 amplification: patients with amplification demonstrated increased stromal CD8⁺ T-cell positivity (P=0.04), as well as significantly elevated intratumoral infiltration of CD68⁺CD163⁺ M2-TAMs (higher density, P=0.03; higher positivity, P=0.03) and increased positivity of CD68⁺HLA-DR⁺ M1-TAMs (P=0.03). These findings indicate that 11q13-amplified tumors may harbor a more complex immunosuppressive and inflammatory microenvironment, potentially contributing to ICI resistance.
Conclusion: Chromosome 11q13 amplification in LIHC is not associated with distinct genomic instability features but is strongly correlated with alterations in the tumor immune microenvironment, including increased CD8⁺ T-cell presence and enrichment of both M1 and M2 tumor-associated macrophages. These results suggest that immune microenvironment dysregulation, rather than genomic variation, may underlie immunotherapy resistance in 11q13-amplified LIHC, underscoring the need for tailored immunotherapeutic strategies for this molecularly defined subgroup.
利益披露 Disclosure
W. Zhu, None.