Tumor-targeted delivery of IL-2 by NKG2D leads to accumulation of antigen-specific CD8+ T cells in the tumor loci and enhanced anti-tumor effects

• Published in: PloS one 2012-04, Vol.7 (4), p.e35141-e35141
• Main Authors: Kang, Tae Heung, Mao, Chih-Ping, He, Liangmei, Tsai, Ya-Chea, Liu, Katherine, La, Victor, Wu, T-C, Hung, Chien-Fu
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antigens; B cells; Biocompatibility; Biology; Cancer; Cancer therapies; Carcinoma, Ovarian Epithelial; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell proliferation; Cytokines; Cytotoxicity; Deoxyribonucleic acid; DNA; Electroporation; Endocrinology; Gaussia; Gene expression; Health aspects; Human papillomavirus; Immune response; Immune response (cell-mediated); Immune system; Immunotherapy; Injections, Intramuscular; Interleukin; Interleukin 2; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Interleukins; Laboratory animals; Ligands; Loci; Luciferase; Luciferases - genetics; Lymphocytes; Lymphocytes T; Medical research; Medicine; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Neoplasms, Experimental - genetics; Neoplasms, Experimental - therapy; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - therapy; NK Cell Lectin-Like Receptor Subfamily K - genetics; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Papillomavirus infections; Pathology; Patients; Proteins; Receptors, IgG - genetics; Recombinant Fusion Proteins - genetics; T cells; Toxicity; Vaccination; Vaccines; Vaccines, DNA - therapeutic use
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035141

Interleukin-2 (IL-2) has been shown to promote tumor-specific T-cell proliferation and differentiation but systemic administration of IL-2 results in significant toxicity. Therefore, a strategy that can specifically deliver IL-2 to the tumor location may alleviate concerns of toxicity. Because NKG2D ligands have been shown to be highly expressed in many cancer cells but not in healthy cells, we reason that a chimeric protein consisting of NKG2D linked to IL-2 will lead to the specific targeting of IL-2 to the tumor location. Therefore, we created chimeric proteins consisting of NKG2D linked to Gaussia luciferase (GLuc; a marker protein) or IL-2 to form NKG2D-Fc-GLuc and NKG2D-Fc-IL2, respectively. We demonstrated that NKG2D linked to GLuc was able to deliver GLuc to the tumor location in vivo. Furthermore, we showed that TC-1 tumor-bearing mice intramuscularly injected with DNA encoding NKG2D-Fc-IL2, followed by electroporation, exhibited an increased number of luciferase-expressing E7-specific CD8+ T cells at the tumor location. More importantly, treatment with the DNA construct encoding NKG2D-Fc-IL2 significantly enhanced the therapeutic anti-tumor effects generated by intradermal vaccination with therapeutic HPV DNA in tumor-bearing mice. Therefore, by linking NKG2D to IL2, we are able to specifically deliver IL-2 to the tumor location, enhancing antigen-specific T-cell immune response and controlling tumor growth. Our approach represents a platform technology to specifically deliver proteins of interest to tumor loci.