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Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival
BACKGROUND: Interleukin(IL)-30/IL-27p28 production by Prostate Cancer (PC) Stem-Like Cells (SLCs) has proven, in murine models, to be critical to tumor onset and progression. In PC patients, IL-30 expression by leukocytes infiltrating PC and draining lymph nodes correlates with advanced disease grad...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670138/ https://www.ncbi.nlm.nih.gov/pubmed/31366386 http://dx.doi.org/10.1186/s40425-019-0668-z |
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author | Sorrentino, Carlo Yin, Zhinan Ciummo, Stefania Lanuti, Paola Lu, Li-Fan Marchisio, Marco Bellone, Matteo Di Carlo, Emma |
author_facet | Sorrentino, Carlo Yin, Zhinan Ciummo, Stefania Lanuti, Paola Lu, Li-Fan Marchisio, Marco Bellone, Matteo Di Carlo, Emma |
author_sort | Sorrentino, Carlo |
collection | PubMed |
description | BACKGROUND: Interleukin(IL)-30/IL-27p28 production by Prostate Cancer (PC) Stem-Like Cells (SLCs) has proven, in murine models, to be critical to tumor onset and progression. In PC patients, IL-30 expression by leukocytes infiltrating PC and draining lymph nodes correlates with advanced disease grade and stage. Here, we set out to dissect the role of host immune cell-derived IL-30 in PC growth and patient outcome. METHODS: PC-SLCs were implanted in wild type (WT) and IL-30 conditional knockout (IL-30KO) mice. Histopathological and cytofluorimetric analyses of murine tumors and lymphoid tissues prompted analyses of patients’ PC samples and follow-ups. RESULTS: Implantation of PC-SLCs in IL-30KO mice, gave rise to slow growing tumors characterized by apoptotic events associated with CD4(+)T lymphocyte infiltrates and lack of CD4(+)Foxp3(+) T regulatory cells (Tregs). IL-30 knockdown in PC-SLCs reduced cancer cell proliferation, vascularization and intra-tumoral Indoleamine 2,3-Dioxygenase (IDO)(+)CD11b(+)Gr-1(+) myeloid-derived cells (MDCs) and led to a significant delay in tumor growth and increase in survival. IL-30-silenced tumors developed in IL-30KO mice, IL-30(−/−)tumors, lacked vascular supply and displayed frequent apoptotic cancer cells entrapped by perforin(+)TRAIL(+)CD3(+)Tlymphocytes, most of which had a CD4(+)T phenotype, whereas IL-10(+)TGFβ(+)Foxp3(+)Tregs were lacking. IL-30 silencing in PC-SLCs prevented lung metastasis in 73% of tumor-bearing WT mice and up to 80% in tumor-bearing IL-30KO mice. In patients with high-grade and locally advanced PC, those with IL-30(−/−)tumors, showed distinct intra-tumoral cytotoxic granule-associated RNA binding protein (TIA-1)(+)CD4(+)Tlymphocyte infiltrate, rare Foxp3(+)Tregs and a lower biochemical recurrence rate compared to patients with IL-30(+/+)tumors in which IL-30 is expressed in both tumor cells and infiltrating leukocytes. CONCLUSION: The lack of host leukocyte-derived IL-30 inhibits Tregs expansion, promotes intra-tumoral infiltration of CD4(+)T lymphocytes and cancer cell apoptosis. Concomitant lack of MDC influx, obtained by IL-30 silencing in PC-SLCs, boosts cytotoxic T lymphocyte activation and cancer cell apoptosis resulting in a synergistic tumor suppression with the prospective benefit of better survival for patients with advanced disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0668-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6670138 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66701382019-08-06 Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival Sorrentino, Carlo Yin, Zhinan Ciummo, Stefania Lanuti, Paola Lu, Li-Fan Marchisio, Marco Bellone, Matteo Di Carlo, Emma J Immunother Cancer Research Article BACKGROUND: Interleukin(IL)-30/IL-27p28 production by Prostate Cancer (PC) Stem-Like Cells (SLCs) has proven, in murine models, to be critical to tumor onset and progression. In PC patients, IL-30 expression by leukocytes infiltrating PC and draining lymph nodes correlates with advanced disease grade and stage. Here, we set out to dissect the role of host immune cell-derived IL-30 in PC growth and patient outcome. METHODS: PC-SLCs were implanted in wild type (WT) and IL-30 conditional knockout (IL-30KO) mice. Histopathological and cytofluorimetric analyses of murine tumors and lymphoid tissues prompted analyses of patients’ PC samples and follow-ups. RESULTS: Implantation of PC-SLCs in IL-30KO mice, gave rise to slow growing tumors characterized by apoptotic events associated with CD4(+)T lymphocyte infiltrates and lack of CD4(+)Foxp3(+) T regulatory cells (Tregs). IL-30 knockdown in PC-SLCs reduced cancer cell proliferation, vascularization and intra-tumoral Indoleamine 2,3-Dioxygenase (IDO)(+)CD11b(+)Gr-1(+) myeloid-derived cells (MDCs) and led to a significant delay in tumor growth and increase in survival. IL-30-silenced tumors developed in IL-30KO mice, IL-30(−/−)tumors, lacked vascular supply and displayed frequent apoptotic cancer cells entrapped by perforin(+)TRAIL(+)CD3(+)Tlymphocytes, most of which had a CD4(+)T phenotype, whereas IL-10(+)TGFβ(+)Foxp3(+)Tregs were lacking. IL-30 silencing in PC-SLCs prevented lung metastasis in 73% of tumor-bearing WT mice and up to 80% in tumor-bearing IL-30KO mice. In patients with high-grade and locally advanced PC, those with IL-30(−/−)tumors, showed distinct intra-tumoral cytotoxic granule-associated RNA binding protein (TIA-1)(+)CD4(+)Tlymphocyte infiltrate, rare Foxp3(+)Tregs and a lower biochemical recurrence rate compared to patients with IL-30(+/+)tumors in which IL-30 is expressed in both tumor cells and infiltrating leukocytes. CONCLUSION: The lack of host leukocyte-derived IL-30 inhibits Tregs expansion, promotes intra-tumoral infiltration of CD4(+)T lymphocytes and cancer cell apoptosis. Concomitant lack of MDC influx, obtained by IL-30 silencing in PC-SLCs, boosts cytotoxic T lymphocyte activation and cancer cell apoptosis resulting in a synergistic tumor suppression with the prospective benefit of better survival for patients with advanced disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40425-019-0668-z) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-31 /pmc/articles/PMC6670138/ /pubmed/31366386 http://dx.doi.org/10.1186/s40425-019-0668-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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 Sorrentino, Carlo Yin, Zhinan Ciummo, Stefania Lanuti, Paola Lu, Li-Fan Marchisio, Marco Bellone, Matteo Di Carlo, Emma Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title | Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title_full | Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title_fullStr | Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title_full_unstemmed | Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title_short | Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
title_sort | targeting interleukin(il)-30/il-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670138/ https://www.ncbi.nlm.nih.gov/pubmed/31366386 http://dx.doi.org/10.1186/s40425-019-0668-z |
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