Esteban-Fabró Roger, Willoughby Catherine E, Piqué-Gili Marta, Montironi Carla, Abril-Fornaguera Jordi, Peix Judit, Torrens Laura, Mesropian Agavni, Balaseviciute Ugne, Miró-Mur Francesc, Mazzaferro Vincenzo, Pinyol Roser, Llovet Josep M
Translational Research in Hepatic Oncology Laboratory, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain.
Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Clin Cancer Res. 2022 Jun 1;28(11):2449-2460. doi: 10.1158/1078-0432.CCR-21-2517.
Immune checkpoint inhibitors combined with antiangiogenic agents produce benefits in the treatment of advanced hepatocellular carcinoma (HCC). We investigated the efficacy and immunomodulatory activity of cabozantinib alone and combined with anti-PD1 in experimental models of HCC, and explored the potential target population that might benefit from this combination.
C57BL/6J mice bearing subcutaneous Hepa1-6 or Hep53.4 tumors received cabozantinib, anti-PD1, their combination, or placebo. Tumor and blood samples were analyzed by flow cytometry, IHC, transcriptome, and cytokine profiling. Cabozantinib-related effects were validated in a colorectal cancer patient-derived xenograft model. Transcriptomic data from three human HCC cohorts (cohort 1: n = 167, cohort 2: n = 57, The Cancer Genome Atlas: n = 319) were used to cluster patients according to neutrophil features, and assess their impact on survival.
The combination of cabozantinib and anti-PD1 showed increased antitumor efficacy compared with monotherapy and placebo (P < 0.05). Cabozantinib alone significantly increased neutrophil infiltration and reduced intratumor CD8+PD1+ T-cell proportions, while the combination with anti-PD1 further stimulated both effects and significantly decreased regulatory T cell (Treg) infiltration (all P < 0.05). In blood, cabozantinib and especially combination increased the proportions of overall T cells (P < 0.01) and memory/effector T cells (P < 0.05), while lowering the neutrophil-to-lymphocyte ratio (P < 0.001 for combination). Unsupervised clustering of human HCCs revealed that high tumor enrichment in neutrophil features observed with the treatment combination was linked to less aggressive tumors with more differentiated and less proliferative phenotypes.
Cabozantinib in combination with anti-PD1 enhanced antitumor immunity by bringing together innate neutrophil-driven and adaptive immune responses, a mechanism of action which favors this approach for HCC treatment.
免疫检查点抑制剂联合抗血管生成药物在晚期肝细胞癌（HCC）治疗中具有显著疗效。我们在HCC实验模型中研究了卡博替尼单独使用以及与抗PD1联合使用的疗效和免疫调节活性，并探索了可能从这种联合治疗中获益的潜在目标人群。
携带皮下Hepa1-6或Hep53.4肿瘤的C57BL/6J小鼠接受卡博替尼、抗PD1、二者联合用药或安慰剂治疗。通过流式细胞术、免疫组化、转录组分析和细胞因子谱分析对肿瘤和血液样本进行检测。在结直肠癌患者来源的异种移植模型中验证了卡博替尼的相关作用。利用来自三个人类HCC队列（队列1：n = 167，队列2：n = 57，癌症基因组图谱：n = 319）的转录组数据，根据中性粒细胞特征对患者进行聚类，并评估其对生存的影响。
与单药治疗和安慰剂相比，卡博替尼与抗PD1联合使用显示出更高的抗肿瘤疗效（P < 0.05）。单独使用卡博替尼可显著增加中性粒细胞浸润并降低肿瘤内CD8 + PD1 + T细胞比例，而与抗PD1联合使用进一步增强了这两种作用，并显著降低调节性T细胞（Treg）浸润（所有P < 0.05）。在血液中，卡博替尼尤其是联合用药增加了总T细胞比例（P < 0.01）和记忆/效应T细胞比例（P < 0.05），同时降低了中性粒细胞与淋巴细胞比例（联合用药时P < 0.001）。对人类HCC进行无监督聚类分析发现，联合治疗观察到的肿瘤中中性粒细胞特征高度富集与侵袭性较低、具有更分化和更低增殖表型的肿瘤相关。
卡博替尼与抗PD1联合使用通过整合先天性中性粒细胞驱动的免疫反应和适应性免疫反应增强了抗肿瘤免疫力，这种作用机制支持了该方法在HCC治疗中的应用。
