Baseline and dynamic cytokines as biomarkers for immune checkpoint and anti-VEGF therapy in advanced hepatocellular carcinoma

Background: Immune checkpoint inhibitors (ICIs), or the combination of ICIs and vascular endothelial growth factor (VEGF) inhibitors, are the preferred treatments for advanced hepatocellular carcinoma (HCC). However, the immunomodulatory effects of anti-VEGF therapy in HCC remain poorly understood. Predictive biomarkers are needed to guide therapy selection. Patients and methods: We prospectively analyzed circulating cytokines in patients with advanced HCC receiving ICIs with or without anti-VEGF inhibitor therapy as standard of care. Serum samples were collected at baseline and ∼2 months after treatment initiation. A 32-cytokine Luminex panel was used to assess systemic immune changes. We examined associations between treatment group, cytokine dynamics, and clinical outcomes. Results: Among 56 enrolled patients, 35 patients were treated with ICIs only (ICI-only), and 21 patients were treated with ICIs plus the VEGF inhibitor bevacizumab (ICI + Bev). Demographic characteristics and treatment outcomes were generally balanced between the two groups. As compared with ICI-only, patients receiving ICI + Bev exhibited significantly reduced fold changes in multiple cytokines on treatment, including sCD40L, macrophage inflammatory protein-1β (MIP-1β), monokine induced by interferon-γ (MIG), and interleukin (IL)-1Ra, of which above-median circulating baseline levels of MIP-1β were associated with inferior clinical outcomes. In addition, patients with above-median circulating levels of IL-6 and IL-12p40 at baseline had longer progression-free survival with ICI + Bev versus ICI-only. Treatment-associated reductions in IL-1Ra, IL-8, IL-18, and VEGF-A were associated with favorable clinical outcomes. Conclusions: In a highly exploratory analysis, myeloid-inflammatory signatures at baseline and treatment-associated reductions in key myeloid cytokines may identify patients most likely to benefit from adding Bev to ICI. Prospective validation of these markers in independent cohorts is warranted.