肿瘤细胞治疗研究
英文原题：Baseline circulating and tumor γδ T cells and early circulating CD8⁺PD1⁺ expansion predict response to Atezolizumab-bevacizumab in HCC.
高基线循环和肿瘤γδ T细胞以及早期循环CD8⁺PD-1⁺ T细胞扩增与AtezoBev治疗下更好的结局相关。循环CD8⁺TIGIT⁺细胞的早期增加与治疗耐药相关。
我们旨在识别在阿替利珠单抗-贝伐珠单抗（AtezoBev）治疗肝细胞癌（HCC）中预测肿瘤学结局的循环和肿瘤免疫特征。
我们开展了一项前瞻性研究，纳入31例接受一线AtezoBev治疗的患者，整合了序贯PBMC免疫表型分析、细胞因子谱分析和全血RNA测序。来自临床试验（GO30140/IMbrave150，209例AtezoBev治疗和58例索拉非尼治疗患者）的肿瘤RNA测序数据，以及163例接受免疫治疗的MSI-H结直肠癌（CRC）数据，被用于评估免疫特征的预测价值。
基于基线时的PBMC分析（87%为男性，年龄65岁，65%为BCLC-C），高基线循环γδ T细胞与疾病控制（p=0.006）和更长的无进展生存期（PFS）（p=0.02）相关。在肿瘤RNA-seq中，高瘤内γδ T特征同样与更高的缓解率（p<0.01）、更长的PFS（p<0.001）和更长的总生存期（p=0.003）相关，且仅限于AtezoBev治疗的患者，而在索拉非尼治疗的患者中则不然。在接受免疫治疗的MSI-H CRC中，高γδ T细胞特征与更长的PFS相关（p=0.034）。循环CD8⁺TIGIT⁺细胞增加与更短的PFS相关（p=0.04），而CD8⁺PD-1⁺细胞增加与更长的PFS相关（p=0.03）。配对转录组分析证实，在出现缓解的患者中，首次注射AtezoBev后3周即早期诱导了T细胞相关的干扰素-γ信号传导。
BACKGROUND: We aimed to identify circulating and tumor immune features predictive of oncological outcomes under Atezolizumab-Bevacizumab (AtezoBev) therapy for hepatocellular carcinoma (HCC). METHODS: We conducted a prospective study in 31 patients treated with first-line AtezoBev, integrating sequential PBMC immunophenotyping, cytokine profiling and whole-blood RNA sequencing. Tumor RNA-sequencing data from clinical trial (GO30140/IMbrave150, 209 AtezoBev and 58 sorafenib-treated patients), together with 163 MSI-H colorectal cancer (CRC) treated by immunotherapy were used to assess the predictive value of immune signatures. RESULTS: Based on PBMC analysis at baseline (87% of male, age 65 years and 65% of BCLC-C), high baseline circulating γδ T-cells was associated with disease control (p=0.006) and longer progression free survival (PFS) (p=0.02). In tumor RNA-seq, a high intratumoral γδ T signature was also associated with higher response (p<0.01), longer PFS (p<0.001), and longer overall survival (p=0.003) exclusively in AtezoBev-treated patients, but not for those treated by sorafenib. In MSI-H CRC treated by immunotherapy, a high γδ T-cell signature was associated with longer PFS (p=0.034). An increase in circulating CD8⁺TIGIT⁺ cells was associated with shorter PFS (p=0.04), whereas an increase in CD8⁺PD-1⁺ cells correlated with longer PFS (p=0.03). Paired transcriptomic analyses confirmed an early induction of T cell-associated interferon-γ signaling at 3 weeks after the first injection of AtezoBev in patients that experienced response. CONCLUSIONS: High baseline circulating and tumor γδ T cells and early circulating CD8⁺PD-1⁺ T Cell expansion were associated with better outcome under AtezoBev. Early increase in circulating CD8⁺TIGIT⁺ cells was associated with treatment resistance.
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