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Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction
BACKGROUND: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting t...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371844/ https://www.ncbi.nlm.nih.gov/pubmed/25806105 http://dx.doi.org/10.1186/s40425-015-0050-8 |
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author | Muthuswamy, Ravikumar Wang, Liwen Pitteroff, Jamie Gingrich, Jeffrey R Kalinski, Pawel |
author_facet | Muthuswamy, Ravikumar Wang, Liwen Pitteroff, Jamie Gingrich, Jeffrey R Kalinski, Pawel |
author_sort | Muthuswamy, Ravikumar |
collection | PubMed |
description | BACKGROUND: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs. METHODS: Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data. RESULTS: Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and T(reg)-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage. CONCLUSIONS: The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-015-0050-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4371844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-43718442015-03-25 Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction Muthuswamy, Ravikumar Wang, Liwen Pitteroff, Jamie Gingrich, Jeffrey R Kalinski, Pawel J Immunother Cancer Research Article BACKGROUND: BCG is a prototypal cancer immunotherapeutic factor currently approved of bladder cancer. In attempt to further enhance the effectiveness of immunotherapy of bladder cancer and, potentially, other malignancies, we evaluated the impact of BCG on local production of chemokines attracting the desirable effector CD8(+) T cells (CTLs) and undesirable myeloid-derived suppressor cell (MDSCs) and regulatory T(reg) cells, and the ability of bladder cancer tissues to attract CTLs. METHODS: Freshly resected bladder cancer tissues were either analyzed immediately or cultured ex vivo in the absence or presence of the tested factors. The expression of chemokine genes, secretion of chemokines and their local sources in freshly harvested and ex vivo-treated tumor explants were analyzed by quantitative PCR (Taqman), ELISAs and immunofluorescence/confocal microscopy. Migration of CTLs was evaluated ex vivo, using 24-transwell plates. Spearman correlation was used for correlative analysis, while paired Students T test or Wilcoxon was used for statistical analysis of the data. RESULTS: Bladder cancer tissues spontaneously expressed high levels of the granulocyte/MDSC-attractant CXCL8 and T(reg)-attractant CCL22, but only marginal levels of the CTL-attracting chemokines: CCL5, CXCL9 and CXCL10. Baseline CXCL10 showed strong correlation with local expression of CTL markers. Unexpectedly, BCG selectively induced only the undesirable chemokines, CCL22 and CXCL8, but had only marginal impact on CXCL10 production. In sharp contrast, the combination of IFNα and a TLR3 ligand, poly-I:C (but not the combinations of BCG with IFNα or BCG with poly-I:C), induced high levels of intra-tumoral production of CXCL10 and promoted CTL attraction. The combination of BCG with IFNα + poly-I:C regimen did not show additional advantage. CONCLUSIONS: The current data indicate that suboptimal ability of BCG to reprogram cancer-associated chemokine environment may be a factor limiting its therapeutic activity. Our observations that the combination of BCG with (or replacement by) IFNα and poly-I:C allows to reprogram bladder cancer tissues for enhanced CTL entry may provide for new methods of improving the effectiveness of immunotherapy of bladder cancer, helping to extend BCG applications to its more advanced forms, and, potentially, other diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40425-015-0050-8) contains supplementary material, which is available to authorized users. BioMed Central 2015-03-24 /pmc/articles/PMC4371844/ /pubmed/25806105 http://dx.doi.org/10.1186/s40425-015-0050-8 Text en © Muthuswamy et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Muthuswamy, Ravikumar Wang, Liwen Pitteroff, Jamie Gingrich, Jeffrey R Kalinski, Pawel Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title | Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title_full | Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title_fullStr | Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title_full_unstemmed | Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title_short | Combination of IFNα and poly-I:C reprograms bladder cancer microenvironment for enhanced CTL attraction |
title_sort | combination of ifnα and poly-i:c reprograms bladder cancer microenvironment for enhanced ctl attraction |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371844/ https://www.ncbi.nlm.nih.gov/pubmed/25806105 http://dx.doi.org/10.1186/s40425-015-0050-8 |
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