title: 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.
abstract: 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.
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Mao
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: Ya-Chea
authors.initials: YC
authors.lastname: Tsai
authors.forename: Katherine
authors.initials: K
authors.lastname: Liu
authors.forename: Victor
authors.initials: V
authors.lastname: La
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D007273:Injections, Intramuscular; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D008024:Ligands; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000628:therapy; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D017452:Receptors, IgG / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D019444:Vaccines, DNA / Q000627:therapeutic use
chemical_list: D007376:Interleukin-2; C527086:Klrk1 protein, mouse; D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D008156:Luciferases