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Sorafenib associated with reduction in immune-suppressive phenotypes in patients with HCC

Sorafenib was associated with a reduction in immune-suppressive phenotypes in patients with hepatocellular carcinoma, according to recent findings published in JCI Insight.

These results suggest that the measurement of these phenotypes before therapy could better identify patients who would benefit from treatment.

“We have shown that redundant immunosuppressive cell types are present at high levels in HCC patients compared with healthy controls and that the number of Tregs, [myeloid derived suppressor cells (MDSC)], and PD-1⁺ exhausted T cells are reduced following sorafenib treatment,” Yasmin Thanavala, PhD, professor of immunology at Roswell Park Cancer Institute in Buffalo, N.Y., and colleagues wrote. “In addition to reduction in the high pretreatment level of these immunosuppressive cell subsets, our most important finding was the association of decrease in PD-1 expression on T cells with improved [overall survival] in patients following sorafenib treatment.”

Yasmin Thanavala

Sorafenib — the current “backbone treatment” for patients with HCC — targets multiple kinase receptors that are expressed on immunosuppressive cell subsets and may reduce the immunosuppressive burden in patients with HCC, which would invigorate antitumor effector T cell function.

Thanavala and colleagues collected blood samples from 19 patients with advanced HCC. They used fluorescence-activated cell sorting to quantify the frequency of PD-1⁺ T cells, Tregs and MDSC. They determined cytokine levels in plasma using enzyme-linked immunosorbent assay.

Researchers found OS was significantly impacted by the reduction of both CD4⁺PD-1⁺ T cells and CD8⁺PD-1⁺ T cells following sorafenib treatment. Further, the ratio of CD4⁺CD127⁺PD^-1^- T effector cells to CD4⁺Foxp3⁺PD^-1⁺ Tregs was significantly increased. They also observed significant decreases in the frequency and absolute number of Foxp3⁺ Tregs as well as a significant improvement in OS for patients showing a greater decrease in the number of Foxp3⁺ Tregs. Increased frequency of CD4⁺CD127⁺ T effector cells in posttreatment was significantly associated with OS.

This study is the first to demonstrate the immunomodulatory effects of sorafenib therapy on PD-1⁺ T cells and Tregs and the correlation with survival, the researchers wrote. The results suggest that finding a higher number of these phenotype cells would identify a patient who would most likely benefit from treatment.

“These signatures could also potentially be used for in vitro assessment of patients most likely to benefit from sorafenib therapy,” the researchers wrote. “Additionally, our studies suggest that administration of sorafenib as a potentially useful adjunct in combination with immunotherapeutic approaches may enhance the therapeutic efficacy of immune-based strategies against advanced malignancies.” – by Will Offit

Disclosure: The researchers report no relevant financial disclosures.