Abstract：
BACKGROUND: The combination of Sorafenib and transcatheter arterial chemoembolization (TACE) exhibits limited efficacy in the treatment of certain advanced hepatocellular carcinomas (HCC), and the molecular mechanisms underlying resistance to this combination remain unclear.
OBJECTIVE: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination.
METHODS: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy.
RESULTS: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1+ tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013).
CONCLUSIONS: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1+ TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results.
OBJECTIVE: This study aims to underscore the distinctive contribution of GeoMx DSP technology in elucidating the molecular intricacies of HCC resistance to the Sorafenib and TACE combination.
METHODS: Patients with advanced HCC during the waiting period before liver transplantation were classified into sensitive and resistant groups based on their response to Sorafenib and TACE combination therapy. Employing GeoMx DSP technology for comprehensive gene expression profiling, we identified pivotal molecular targets linked to resistance against combination therapy.
RESULTS: The investigation scrutinized intra-tumoral and inter-individual variances, unveiling a spectrum of crucial molecular targets, such as PLG, PLVAP, immunoglobulin genes, ORM1, and NR4A1, among others. Additionally, we explored signaling pathways associated with treatment responsiveness, including the PPAR signaling pathway. Notably, we emphasized the significance of the immune microenvironment characterized by heightened SPP1 expression in HCC resistance to combination therapy. In the resistant group, SPP1+ tumor-associated macrophage (TAM) infiltration was notably pronounced (p = 0.037), while T-cell depletion showed a mitigated presence (p = 0.013).
CONCLUSIONS: The study reveals intra- and inter-individual heterogeneity in HCC that is differentially responsive to the combination of Sorafenib and TACE, highlighting multiple key molecular targets associated with treatment resistance. The immune microenvironment is important, and in particular, SPP1+ TAM infiltration may play a key role. Meanwhile, the introduction of immunotherapy in patients resistant to combination therapy may lead to positive results.
摘要：
背景：索拉非尼和经导管动脉化疗栓塞（TACE）的组合在某些晚期肝细胞癌（HCC）的治疗中表现出有限的疗效，对这种组合产生抗性的分子机制尚不清楚。
目的：本研究旨在强调GeoMxDSP技术在阐明HCC对索拉非尼和TACE联合耐药的分子复杂性方面的独特贡献。
方法：根据对索拉非尼和TACE联合治疗的反应，将肝移植前等待期的晚期HCC患者分为敏感组和耐药组。采用GeoMxDSP技术进行全面的基因表达谱分析，我们确定了与联合治疗耐药相关的关键分子靶点.
结果：调查仔细检查了肿瘤内和个体间的差异，揭示了一系列关键分子目标，如PLG，PLVAP,免疫球蛋白基因，ORM1和NR4A1等。此外,我们探索了与治疗反应性相关的信号通路，包括PPAR信号通路。值得注意的是,我们强调了以SPP1表达增强为特征的免疫微环境在HCC对联合治疗耐药中的重要性.在抗性组中，SPP1+肿瘤相关巨噬细胞(TAM)浸润显著(p=0.037),而T细胞耗竭显示存在减轻（p=0.013）。
结论：该研究揭示了对索拉非尼和TACE的组合有不同反应的HCC的个体内和个体间异质性，突出与治疗抗性相关的多个关键分子靶标。免疫微环境很重要,特别是,SPP1+TAM浸润可能起关键作用。同时,在对联合治疗耐药的患者中引入免疫治疗可能会产生积极的结果.
目的：本研究旨在强调GeoMxDSP技术在阐明HCC对索拉非尼和TACE联合耐药的分子复杂性方面的独特贡献。
方法：根据对索拉非尼和TACE联合治疗的反应，将肝移植前等待期的晚期HCC患者分为敏感组和耐药组。采用GeoMxDSP技术进行全面的基因表达谱分析，我们确定了与联合治疗耐药相关的关键分子靶点.
结果：调查仔细检查了肿瘤内和个体间的差异，揭示了一系列关键分子目标，如PLG，PLVAP,免疫球蛋白基因，ORM1和NR4A1等。此外,我们探索了与治疗反应性相关的信号通路，包括PPAR信号通路。值得注意的是,我们强调了以SPP1表达增强为特征的免疫微环境在HCC对联合治疗耐药中的重要性.在抗性组中，SPP1+肿瘤相关巨噬细胞(TAM)浸润显著(p=0.037),而T细胞耗竭显示存在减轻（p=0.013）。
结论：该研究揭示了对索拉非尼和TACE的组合有不同反应的HCC的个体内和个体间异质性，突出与治疗抗性相关的多个关键分子靶标。免疫微环境很重要,特别是,SPP1+TAM浸润可能起关键作用。同时,在对联合治疗耐药的患者中引入免疫治疗可能会产生积极的结果.
