Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival
Abstract 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 dise...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0668-z |
| _version_ | 1828847009844428800 |
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| author | Carlo Sorrentino Zhinan Yin Stefania Ciummo Paola Lanuti Li-Fan Lu Marco Marchisio Matteo Bellone Emma Di Carlo |
| author_facet | Carlo Sorrentino Zhinan Yin Stefania Ciummo Paola Lanuti Li-Fan Lu Marco Marchisio Matteo Bellone Emma Di Carlo |
| author_sort | Carlo Sorrentino |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T21:59:34Z |
| format | Article |
| id | doaj.art-3f17e414dd4549db9060d89133e064b6 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-12T21:59:34Z |
| publishDate | 2019-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-3f17e414dd4549db9060d89133e064b62022-12-22T00:10:33ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-07-017111510.1186/s40425-019-0668-zTargeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survivalCarlo Sorrentino0Zhinan Yin1Stefania Ciummo2Paola Lanuti3Li-Fan Lu4Marco Marchisio5Matteo Bellone6Emma Di Carlo7Department of Medicine and Sciences of Aging, G. d’Annunzio University of Chieti-PescaraThe First Affiliated Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan UniversityDepartment of Medicine and Sciences of Aging, G. d’Annunzio University of Chieti-PescaraDepartment of Medicine and Sciences of Aging, G. d’Annunzio University of Chieti-PescaraDivision of Biological Sciences, Center for Microbiome Innovation and Moores Cancer Center, University of CaliforniaDepartment of Medicine and Sciences of Aging, G. d’Annunzio University of Chieti-PescaraCellular Immunology Unit, San Raffaele Scientific InstituteDepartment of Medicine and Sciences of Aging, G. d’Annunzio University of Chieti-PescaraAbstract 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.http://link.springer.com/article/10.1186/s40425-019-0668-zInterleukin-30Tumor microenvironmentProstate Cancer Stem-Like CellsTreg cellsImmunohistochemistry |
| spellingShingle | Carlo Sorrentino Zhinan Yin Stefania Ciummo Paola Lanuti Li-Fan Lu Marco Marchisio Matteo Bellone Emma Di Carlo Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival Journal for ImmunoTherapy of Cancer Interleukin-30 Tumor microenvironment Prostate Cancer Stem-Like Cells Treg cells Immunohistochemistry |
| 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 | Interleukin-30 Tumor microenvironment Prostate Cancer Stem-Like Cells Treg cells Immunohistochemistry |
| url | http://link.springer.com/article/10.1186/s40425-019-0668-z |
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