Activated Lymphocytes and Increased Risk of Dermatologic Adverse Events during Sorafenib Therapy for Hepatocellular Carcinoma

Simple Summary Hepatocellular carcinoma is the second cause of cancer-related death worldwide. Of those advanced-stage patients who are treated with sorafenib, those who develop early dermatologic adverse events have a better prognosis. These events are possibly immune-related. Therefore, we analyzed the phenotype of 52 sorafenib-treated patients' circulating lymphocytes throughout treatment. We found that different co-stimulatory and immune exhaustion markers, such as Programmed cell death protein 1 (PD-1) and DNAX accessory molecule 1 (DNAM-1) amongst others, correlate with the probability of developing these adverse events, both before and during the treatment. We also compared the phenotype of those lymphocytes expressing DNAM-1 with those that do not, and while NK DNAM-1-expressing cells have a co-stimulatory phenotype, T DNAM-1-expressing cells are immune-suppressors. Overall, we set a rationale for the combination of sorafenib and immune-targeted therapies; and for the use of immune markers (such as DNAM-1) for patients' prognosis evaluation. Advanced hepatocellular carcinoma patients treated with sorafenib who develop early dermatologic adverse events (eDAEs) have a better prognosis. This may be linked to immune mechanisms, and thus, it is relevant to assess the association between peripheral immunity and the probability of developing eDAEs. Peripheral blood mononuclear cells of 52 HCC patients treated with sorafenib were analyzed at baseline and throughout the first eight weeks of therapy. T, B, Natural Killer cells, and their immune checkpoints expression data were characterized by flow cytometry. Cytokine release and immune-suppression assays were carried out ex vivo. Cox baseline and time-dependent regression models were applied to evaluate the probability of increased risk of eDAEs. DNAM-1, PD-1, CD69, and LAG-3 in T cells, plus CD16 and LAG-3 in NK cells, are significantly associated with the probability of developing eDAEs. While NK DNAM-1(+) cells express activation markers, T DNAM-1(+) cells induce immune suppression and show immune exhaustion. This is the first study to report an association between immune checkpoints expression in circulating immune cells and the increased incidence of eDAEs. Our results support the hypothesis for an off-target role of sorafenib in immune modulation. We also describe a novel association between DNAM-1 and immune exhaustion in T cells.

Automated summary

Hepatocellular carcinoma is the second leading cause of cancer-related deaths worldwide. Patients with advanced-stage who develop early dermatologic adverse events while treated with sorafenib have a better prognosis, possibly due to immune mechanisms. Immune markers like PD-1 and DNAM-1 correlate with the development of these adverse events. NK DNAM-1-expressing cells exhibit an activation phenotype, while T DNAM-1-expressing cells induce immune suppression and exhaustion.