Sorafenib attenuated the function of natural killer cells infiltrated in HCC through inhibiting ERK1/2

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Sorafenib is a standard therapy for advanced hepatocellular carcinoma (HCC).
• Natural killer (NK) cells are crucial cytotoxic lymphocytes in liver and tumor immunity.
• The impact of Sorafenib on NK cell function remains largely unknown.

Purpose of the Study:

• To investigate the effects of Sorafenib on the number and function of NK cells in HCC.
• To elucidate the underlying mechanisms by which Sorafenib influences NK cells.

Main Methods:

• Utilized subcutaneous and in situ mouse models of HCC (hepa 1-6 cell line).
• Analyzed NK cell populations and functions in blood, liver, tumor, and draining lymph nodes via flow cytometry (FACS), ELISA, and Western blot.
• Performed in vitro experiments on sorted NK cells, assessing functions and molecular mechanisms (qPCR, Western blot, FACS) after Sorafenib stimulation.

Main Results:

• Sorafenib significantly inhibited tumor progression but decreased NK cell numbers by suppressing proliferation.
• Sorafenib treatment reduced NK cell effector functions, including decreased production of perforin, granzyme B, TNF-α, and IFN-γ.
• Sorafenib inhibited p-ERK1/2 phosphorylation in NK cells; ERK1/2 inhibition mimicked Sorafenib's effects on NK cells.

Conclusions:

• Sorafenib suppresses NK cell proliferation and effector functions, contributing to its anti-tumor effects in HCC.
• The ERK1/2 signaling pathway is a key mediator of Sorafenib's inhibitory effects on NK cell number and function.
• These findings highlight Sorafenib's immunomodulatory role and suggest potential therapeutic strategies targeting NK cells in HCC.