HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD-1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma.
Many tumor immunotherapy efforts are focused on the generation of strong T-cell response against tumor antigens. However, strong T-cell response does not always coincide with tumor rejection, for which upregulated expression of immunoinhibitory molecules may be responsible. In this study, the treatment with heat shock protein 70 (HSP70) vaccine induced an infiltration of T cells into the tumor site as well as the expression of IFN-gamma and IL-2, and delayed lung metastases of tumor, but the tumor progression nonetheless occur finally. We demonstrated that B7-H1 expressed by residual tumor cells was responsible for the resistance of tumor to the therapy with HSP70 vaccine. Blockade of B7-H1 by i.v. injection pPD-1A, a plasmid encoding the extracellular domain of PD-1 (sPD-1), could reverse this resistance and enhance the therapeutic efficacy. To complement these findings, we investigated the gene expression of tumor-infiltrating lymphocytes (TILs) by Real-time PCR analysis, which revealed that the expression of TH1 cytokines IFN-gamma and IL-2 by TIL in the mice treated with HSP70 vaccine in combination with sPD-1 was increased and the expression of negative regulatory molecules IL-10, TGF-beta and foxp3 was decreased, demonstrating that multifunctional properties afforded by the combination therapy can effectively overcome tumor resistance and promote effective antitumor immunity. The in vivo transfection with pPD-1A could be performed as infrequently as once a week and still produce a significant antitumor effect. These findings suggest that the treatment with HSP70 vaccine followed by blockade of tumor-B7-H1 with sPD-1 may provide a promising approach for tumor immunotherapy.
Geng
Hui
H
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, The People's Republic of China.
Zhang
Gui-Mei
GM
Xiao
Han
H
Yuan
Ye
Y
Li
Dong
D
Zhang
Hui
H
Qiu
Hui
H
He
Yu-Fei
YF
Feng
Zuo-Hua
ZH
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000502:physiology; D000943:Antigens, Differentiation / Q000276:immunology; D060890:B7-H1 Antigen; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology* / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma