HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD‐1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma

• Published in: International journal of cancer 2006-06, Vol.118 (11), p.2657-2664
• Main Authors: Geng, Hui, Zhang, Gui‐Mei, Xiao, Han, Yuan, Ye, Li, Dong, Zhang, Hui, Qiu, Hui, He, Yu‐Fei, Feng, Zuo‐Hua
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - biosynthesis; Antigens, CD - physiology; Antigens, Differentiation - immunology; B7-H1 Antigen; Biological and medical sciences; Cancer Vaccines - immunology; Female; gene therapy; Genetic Therapy; HSP70 Heat-Shock Proteins - immunology; HSP70 Heat-Shock Proteins - therapeutic use; immune escape; Immunotherapy - methods; Interferon-gamma - biosynthesis; Interleukin-2 - biosynthesis; Lung Neoplasms - immunology; Lung Neoplasms - secondary; Lung Neoplasms - therapy; Medical sciences; Melanoma - immunology; Melanoma - secondary; Melanoma - therapy; Mice; Mice, Inbred C57BL; Other treatments; Programmed Cell Death 1 Receptor; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; T-Lymphocytes - immunology; Treatment. General aspects; tumor immunity; tumor immunotherapy; Tumors; Up-Regulation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.21795

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‐γ 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‐γ 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‐β 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. © 2006 Wiley‐Liss, Inc.