title: Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity.
abstract: Despite its potent immunostimulatory properties, vaccination with autologous tumor-derived gp96 has relatively modest antitumor effect in a range of clinical trials. Based on our previous study showing a gp96-mediated immune balance between CTL and Tregs, here we investigated possible synergy between gp96 vaccine and systemic Treg depletion on induction of antitumor T-cell immunity and the mechanisms accounting for synergistic efficacy. In gp96-peptide complex immunized BALB/c mice, anti-CD25 mAb treatment significantly increased IFN-γ-producing CD8(+) and CD4(+) T cells by about 1-2-fold in spleen and 40-50% in lymph node. A significantly higher number of peptide-specific CTL were observed under anti-CD25 mAb treatment compared with no treatment. Moreover, Treg depletion synergistically improved the anticancer activity of tumor-derived gp96 vaccine in the poorly immunogenic and highly tumorigenic B16 melanoma model in C57BL/6 J mice. While gp96 immunization alone led to the modest enhancement of CTL activities in spleen, the combination with Treg depletion dramatically increased tumor-specific CTL responses. In addition, the combination resulted in a significant increase of CD8(+) T-cell infiltration in tumor, which correlated with an enhanced inhibition of tumor growth. Our results provide evidence that targeting Tregs may provide a more efficient strategy to potentiate gp96-mediated T-cell responses and enhance the antitumor efficiency of gp96-based therapeutic vaccine.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, NO.1 West Beichen Road, Chaoyang District, Beijing 100101, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Yan
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinghui
authors.initials: X
authors.lastname: Li
authors.forename: Saifeng
authors.initials: S
authors.lastname: Wang
authors.forename: Bao
authors.initials: B
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Ju
authors.forename: Lizhao
authors.initials: L
authors.lastname: Chen
authors.forename: Wenjun
authors.initials: W
authors.lastname: Liu
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D008562:Membrane Glycoproteins; C053387:endoplasmin