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Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model
Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they ar...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348754/ https://www.ncbi.nlm.nih.gov/pubmed/32224883 http://dx.doi.org/10.3390/vaccines8020147 |
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author | Gąbka-Buszek, Agnieszka Kwiatkowska-Borowczyk, Eliza Jankowski, Jakub Kozłowska, Anna Karolina Mackiewicz, Andrzej |
author_facet | Gąbka-Buszek, Agnieszka Kwiatkowska-Borowczyk, Eliza Jankowski, Jakub Kozłowska, Anna Karolina Mackiewicz, Andrzej |
author_sort | Gąbka-Buszek, Agnieszka |
collection | PubMed |
description | Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they are targets for various cancer therapies, including immunotherapy. Here, we demonstrate the effectiveness of melanoma vaccines composed of genetically modified tumor cells admixed with melanoma stem-like cells (MSC) or induced pluripotent stem cells (iPSCs). Two vaccines were constructed. The first vaccine contained cells derived from B16F10 melanospheres (SFs) with CSC characteristics. The second vaccine contained syngeneic murine induced pluripotent stem cells (miPSCs). iPSCs or SF cells were admixed with B16F10 cells, modified with the designer cytokine Hyper-IL6(H6) (B16/H6). Control mice received B16/H6 cells, B16F10 cells or PBS. Immunization with either vaccine significantly inhibited tumor growth and increased disease-free survival (DFS) and overall survival (OS) in C57BL/6 mice. Mice treated with the SF or iPSC vaccine demonstrated increased activation of the immune response in the vaccination site and tumor microenvironment compared to those treated with B16/H6, B16F10 or PBS. Higher infiltration of dendritic cells (DCs) monocytes, and natural killer (NK) cells; lower numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); higher levels of the cytokines INFγ and IL-12 were observed with the novel vaccines than with the control treatments. In vitro restimulation of splenocytes derived from mice immunized with B16F10 cell, SF cell or miPSC lysates increased the proliferation of CD4+ T helper lymphocytes and secretion of cytokines. An increased serum titer of antibodies directed against B16F10 cells was found in mice immunized with the SF vaccine. The most effective DFS and OS extensions were reached with the miPSCs vaccine. The described results form the basis for a novel platform for the next generation of cancer vaccines composed of allogeneic cancer-specific cells modified with a molecular adjuvant gene and admixed with allogeneic miPSCs or SFs. |
format | Online Article Text |
id | pubmed-7348754 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-73487542020-07-20 Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model Gąbka-Buszek, Agnieszka Kwiatkowska-Borowczyk, Eliza Jankowski, Jakub Kozłowska, Anna Karolina Mackiewicz, Andrzej Vaccines (Basel) Article Therapeutic cancer vaccines have elicited renewed interest due to the development of immune checkpoint inhibitors. The role of these vaccines is to induce specific effector cells for killing cancer cells. Cancer stem cells (CSCs) are responsible for tumor growth and progression. Accordingly, they are targets for various cancer therapies, including immunotherapy. Here, we demonstrate the effectiveness of melanoma vaccines composed of genetically modified tumor cells admixed with melanoma stem-like cells (MSC) or induced pluripotent stem cells (iPSCs). Two vaccines were constructed. The first vaccine contained cells derived from B16F10 melanospheres (SFs) with CSC characteristics. The second vaccine contained syngeneic murine induced pluripotent stem cells (miPSCs). iPSCs or SF cells were admixed with B16F10 cells, modified with the designer cytokine Hyper-IL6(H6) (B16/H6). Control mice received B16/H6 cells, B16F10 cells or PBS. Immunization with either vaccine significantly inhibited tumor growth and increased disease-free survival (DFS) and overall survival (OS) in C57BL/6 mice. Mice treated with the SF or iPSC vaccine demonstrated increased activation of the immune response in the vaccination site and tumor microenvironment compared to those treated with B16/H6, B16F10 or PBS. Higher infiltration of dendritic cells (DCs) monocytes, and natural killer (NK) cells; lower numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs); higher levels of the cytokines INFγ and IL-12 were observed with the novel vaccines than with the control treatments. In vitro restimulation of splenocytes derived from mice immunized with B16F10 cell, SF cell or miPSC lysates increased the proliferation of CD4+ T helper lymphocytes and secretion of cytokines. An increased serum titer of antibodies directed against B16F10 cells was found in mice immunized with the SF vaccine. The most effective DFS and OS extensions were reached with the miPSCs vaccine. The described results form the basis for a novel platform for the next generation of cancer vaccines composed of allogeneic cancer-specific cells modified with a molecular adjuvant gene and admixed with allogeneic miPSCs or SFs. MDPI 2020-03-26 /pmc/articles/PMC7348754/ /pubmed/32224883 http://dx.doi.org/10.3390/vaccines8020147 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gąbka-Buszek, Agnieszka Kwiatkowska-Borowczyk, Eliza Jankowski, Jakub Kozłowska, Anna Karolina Mackiewicz, Andrzej Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title | Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title_full | Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title_fullStr | Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title_full_unstemmed | Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title_short | Novel Genetic Melanoma Vaccines Based on Induced Pluripotent Stem Cells or Melanosphere-Derived Stem-Like Cells Display High Efficacy in a murine Tumor Rejection Model |
title_sort | novel genetic melanoma vaccines based on induced pluripotent stem cells or melanosphere-derived stem-like cells display high efficacy in a murine tumor rejection model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348754/ https://www.ncbi.nlm.nih.gov/pubmed/32224883 http://dx.doi.org/10.3390/vaccines8020147 |
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