Augmentation of IFN-γ+ CD8+ T cell responses correlates with survival of HCC patients on sorafenib therapy

BACKGROUND. Sorafenib has been shown to reduce the extent of immunosuppression in patients with hepatocellular carcinoma (HCC). The rationale of this investigation was to identify biomarkers that can predict treatment efficacy of sorafenib in HCC patients and to unravel the mechanism by which sorafenib impedes immune suppression mediated by distinct immunosuppressive cell subsets. METHODS. With informed consent, blood samples were collected from 30 patients with advanced HCC, at baseline and 2 time points after initiation of sorafenib treatment. The frequency of PD-1(+) T cells, ERK2 phosphorylation on flt-3(+) Tregs and MDSCs, and T effector cell function were quantified by using flow cytometry. RESULTS. Elevated levels of CD8(+)Ki67(+) T cells producing IFN-gamma were associated with improved progression-free survival and overall survival (OS). High frequencies of these T cells were correlated with significantly reduced risk of death over time. Patients with an increased pretreatment T effector/Treg ratio showed significant improvement in OS. ERK(+)flt-3(+) Tregs and MDSCs were significantly decreased after sorafenib therapy, Increased numbers of baseline flt-3(+) p-ERK+ MDSCs were associated with survival benefit of patients. CONCLUSION. A high baseline CD4(+) T effector/Treg ratio is a potential biomarker of prognostic significance in HCC. CD8(+)Ki67(+) T cells producing IFN-gamma are a key biomarker of response to sorafenib therapy resulting in survival benefit. The immune modulation resulted from sorafenib-mediated blockade of signaling through the VEGF/VEGFR/flt-3 pathway, affecting ERK phosphorylation. These insights may help identify patients who likely would benefit from VEGFR antagonism and inform efforts to improve the efficacy of sorafenib in combination with immunotherapy.