Sorafenib, a multitargeted antiangiogenic
tyrosine kinase inhibitor, is the standard of care for patients with advanced
hepatocellular carcinoma (HCC). Cumulating evidence suggests that
sorafenib differentially affects immune cells; however, whether this immunomodulatory effect has any impact on antitumor immune responses is unknown. Using an orthotopic mouse model of HCC and
tumor-free mice, we investigated the effects of
sorafenib on antitumor immunity and characterized the underlying mechanisms.
Sorafenib treatment inhibited
tumor growth and augmented antitumor immune responses in mice bearing established orthotopic HCC. The
tumor-specific effector T cell functions were upregulated, while the proportion of PD-1-expressing CD8(+) T cells and regulatory T cells (Tregs) was reduced in tumor microenvironment of
sorafenib-treated mice. Mechanistically, the
sorafenib-mediated effects on Tregs could be independent of its direct
tumor-suppressing activities.
Sorafenib treatment reduced Treg numbers by inhibiting their proliferation and inducing apoptosis. Moreover,
sorafenib inhibited the function of Tregs, characterized by diminished expression of Treg-associated molecules important for their function and by their impaired suppressive capacity. These data reveal that
sorafenib treatment enhanced functions of
tumor-specific effector T cells as well as relieved PD-1-mediated intrinsic and Treg-mediated non-cell-autonomous inhibitions in tumor microenvironment leading to effective antitumor immune responses. In addition to the well-known
tumor-inhibiting activity of
sorafenib, its enhancement of antitumor immunity may also contribute to the clinical efficacy. Our findings uncover a previously unrecognized mechanism of action of
sorafenib and indicate that
sorafenib represents a potential targeted agent suitable to be combined with immunotherapeutic approaches to treat
cancer patients.