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.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/immunology , Liver Neoplasms, Experimental/immunology , Niacinamide/analogs & derivatives , Phenylurea Compounds/pharmacology , T-Lymphocytes, Regulatory/immunology , Tumor Microenvironment/immunology , Animals , Apoptosis , Blotting, Western , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Proliferation , Flow Cytometry , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/pathology , Lymphocytes, Tumor-Infiltrating/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Niacinamide/pharmacology , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sorafenib , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/pathology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/pathology , Tumor Cells, Cultured , Tumor Microenvironment/drug effectsABSTRACT
Exposure to sub-lethal levels of stress, or hormesis, was a means to induce longevity. By screening for mutations that enhance resistance to multiple stresses, we identified multiple alleles of alpha-1,2-mannosidase I (mas1) which, in addition to promoting stress resistance, also extended longevity. Longevity enhancement is also observed when mas1 expression is reduced via RNA interference in both Drosophila melanogaster and Caenorhabditis elegans. The screen also identified Edem1 (Edm1), a gene downstream of mas1, as a modulator of lifespan. As double mutants for both mas1 and Edm1 showed no additional longevity enhancement, it appeared that both mutations function within a common pathway to extend lifespan. Molecular analysis of these mutants revealed that the expression of BiP, a putative biomarker of dietary restriction (DR), is down-regulated in response to reductions in mas1 expression. These findings suggested that mutations in mas1 may extend longevity by modulating DR.
