Document resource
Background Immune checkpoint inhibition (ICI) and anti-angiogenic therapies including multikinase inhibitors are active in advanced hepatocellular carcinoma (HCC), though only a subset of patients achieved durable responses. Combined inhibition of myelosuppressive immune cells and angiogenesis in the tumor microenvironment may reduce primary resistance and augment response. However, patients with greater underlying liver dysfunction, as measured by the Child-Pugh score, have lower rates of objective response and shorter median overall survival. Understanding immune dysfunction related to liver disease is needed to improve the success of immunotherapy in this population.Methods We conducted a multi-center, open-label clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with ICI nivolumab (anti-PD-1), in 16 patients with HCC and Child-Pugh A (CPA, n=10) or B (CPB, n=6) liver function (NCT0343891). Clinical benefit was defined as radiographic partial or complete response or progression-free survival (PFS) duration of at least 6 months. For correlative immune profiling, peripheral blood mononuclear cells (PBMC) were obtained from patients at enrollment and 3 weeks post-treatment and were analyzed by high-resolution single-cell transcriptomics and proteomics to unbiasedly assess circulating immune cell populations.Results We previously found a population of CD14 + monocytes, CD14CTX, to be suppressive of anti-tumor immune responses in other liver tumors; in this HCC cohort, CD14CTX showed upregulation of genes involved in TGFb and Wnt-beta catenin signaling, angiogenesis, epithelial-mesenchymal transition, and hypoxia. Among 14 patients with serial PBMCs, single-cell analysis demonstrated that there was a higher proportion of pre-treatment CD14CTX in CPB than in CPA. Patients with clinical benefit (n=2) had decreased levels of immunosuppressive CD14CTX with treatment. While the frequency of CD14CTX remained low in the patients with CPA liver function prior to and following treatment, there was a trend towards a decrease in CD14CTX with treatment in CPB. Investigating gene expression profiles of CD4+ and CD8+ T cells revealed elevated TGFb signaling and angiogenesis, and downregulated IFNa and IFNg pathways in patients with CPB compared to CPA. Furthermore, the frequency of effector T cell populations negatively correlated with CD14CTX, suggesting crosstalk between suppressive monocytes and T cells.Conclusions Enrichment of immunosuppressive CD14 CTX was observed in patients with HCC and CPB but not CPA liver disease, indicating a potential mechanism of treatment resistance in patients with worse liver dysfunction in this small cohort. Targeting CD14+ monocytes to reverse myeloid-mediated suppression warrants investigation to improve immunotherapy responses in patients with HCC and liver dysfunction.Acknowledgements This work was supported by Bayer, BMS, the Bili Project Foundation, Inc., the imCORE Network through Genentech Inc, and National Institutes of Health grants 1K12CA260225-01 and K08CA290152.Trial Registration NCT0343891Consent This study was approved and overseen by the UCSF Institutional Review Board.