Cargando…
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
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...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324421/ https://www.ncbi.nlm.nih.gov/pubmed/22509395 http://dx.doi.org/10.1371/journal.pone.0035141 |
_version_ | 1782229309471064064 |
---|---|
author | Kang, Tae Heung Mao, Chih-Ping He, Liangmei Tsai, Ya-Chea Liu, Katherine La, Victor Wu, T.-C. Hung, Chien-Fu |
author_facet | Kang, Tae Heung Mao, Chih-Ping He, Liangmei Tsai, Ya-Chea Liu, Katherine La, Victor Wu, T.-C. Hung, Chien-Fu |
author_sort | Kang, Tae Heung |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3324421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33244212012-04-16 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 Kang, Tae Heung Mao, Chih-Ping He, Liangmei Tsai, Ya-Chea Liu, Katherine La, Victor Wu, T.-C. Hung, Chien-Fu PLoS One Research Article 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. Public Library of Science 2012-04-11 /pmc/articles/PMC3324421/ /pubmed/22509395 http://dx.doi.org/10.1371/journal.pone.0035141 Text en Kang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kang, Tae Heung Mao, Chih-Ping He, Liangmei Tsai, Ya-Chea Liu, Katherine La, Victor Wu, T.-C. Hung, Chien-Fu 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 |
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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324421/ https://www.ncbi.nlm.nih.gov/pubmed/22509395 http://dx.doi.org/10.1371/journal.pone.0035141 |
work_keys_str_mv | AT kangtaeheung tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT maochihping tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT heliangmei tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT tsaiyachea tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT liukatherine tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT lavictor tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT wutc tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects AT hungchienfu tumortargeteddeliveryofil2bynkg2dleadstoaccumulationofantigenspecificcd8tcellsinthetumorlociandenhancedantitumoreffects |