Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity
Journal
International Journal of Cancer
Journal Volume
134
Journal Issue
2
Pages
319-331
Date Issued
2014
Author(s)
Abstract
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. ? 2013 UICC.
SDGs
Other Subjects
sorafenib; animal cell; animal experiment; animal model; apoptosis; article; cancer chemotherapy; cancer inhibition; CD8+ T lymphocyte; cell function; cellular immunity; controlled study; down regulation; drug efficacy; drug mechanism; drug targeting; liver cell carcinoma; lymphocyte proliferation; mouse; nonhuman; priority journal; regulatory T lymphocyte; tumor growth; tumor immunity; tumor microenvironment; upregulation; antitumor immunity; orthotopic mouse model; PD-1; Tregs; tyrosine kinase inhibitor; Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Proliferation; Flow Cytometry; Liver Neoplasms, Experimental; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Niacinamide; Phenylurea Compounds; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory; Tumor Cells, Cultured; Tumor Microenvironment
Type
journal article