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Theranostics 2016; 6(5):752-761. doi:10.7150/thno.14527 This issue Cite

Research Paper

Folate-modified Chitosan Nanoparticles Containing the IP-10 Gene Enhance Melanoma-specific Cytotoxic CD8⁺CD28⁺ T Lymphocyte Responses

Jian He^1,*, Siliang Duan^1,*, Xia Yu^1,*, Zhiyong Qian², Sufang Zhou¹, Zhiyong Zhang³, Xianing Huang¹, Yong Huang¹, Jing Su¹, Chunhui Lai¹, Jinyu Meng⁴, Nuo Zhou^1✉, Xiaoling Lu^1,5✉, Yongxiang Zhao^1✉

1. National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China;
2. State Key Laboratory for Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China.
3. Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08901, USA.
4. Biomedical Polymers Laboratory, Soochow University, Suzhou, Jiangsu 215123, China;
5. The Department of Immunology, Guangxi Medical University, Nanning, Guangxi 530021, China.
* These authors contributed equally to this work.

✉ Corresponding authors: Yongxiang Zhao, M.D., Ph.D., Professor, National Center for International Research of Biological Targeting Diagnosis and Therapy / Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research / Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China. Tel: (86) 771-5317 061; Fax: (86) 771-5317 061 E-mail: yongxiang_zhaocom Other corresponding authors: Xiaoling Lu, Ph.D., Professor, National Center for International Research of Biological Targeting Diagnosis and Therapy / Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research / Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China. Tel: (86) 771-5317 061; Fax: (86) 771-5317 061 Email: luwuliucom Nuo Zhou, M.D., Ph.D., Professor, Department of Oral and Maxillofacial Surgery, the Affiliated Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi 530021, China. Tel: (86) 771-5317 061; Fax: (86) 771-5317 061 E-mail: nuozhoucom. More

Abstract

Background: Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) has great potential for the treatment of some malignant cancers. Therefore, augmenting the responses of tumor-specific CTLs is significant for the adoptive immunotherapy of melanoma. This study aimed to investigate the anti-tumor response of a combination therapy employing folate-modified chitosan nanoparticles containing IP-10 (interferon-γ-inducible protein-10) plus melanoma TRP2-specific CD8⁺CD28⁺ T cells. Methods: We prepared folate-modified chitosan nanoparticles containing the mouse IP-10 gene (FA-CS-mIP-10), and induced melanoma TRP2-specific CD8⁺CD28⁺ T cells by co-culturing them with artificial antigen-presenting cells. B16-bearing mice were treated with FA-CS-mIP-10, melanoma TRP2-specific CD8⁺CD28⁺ T cells, a combination of both, and the saline control. Tumor volumes and the survival time of mice were recorded. The proportion of myeloid-derived suppressor cells (MDSCs) infiltrating the tumor microenvironment and regulatory T cells (Tregs) in the spleen was analyzed by flow cytometry. We also detected the proliferation and angiogenesis of tumors by immunohistochemistry and apoptosis by TUNEL. Results: The combination therapy inhibited the progression of melanoma in vivo. Compared with other treatments, it more efficiently inhibited tumor growth and increased the survival time of mice. After treatment with combination therapy, the proportion of MDSCs and Tregs decreased, while the percentage of CXCR3⁺CD8⁺ T cells increased. Furthermore, combination therapy inhibited proliferation and promoted apoptosis of tumor cells and significantly inhibited tumor angiogenesis in vivo. Conclusion: We describe a novel strategy for improving the anti-tumor response of CD8⁺CD28⁺ CTLs by combining them with FA-CS-mIP-10 nanoparticles.

Keywords: cytotoxic T lymphocytes, melanoma, folate, chitosan, interferon-γ-inducible protein-10.

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