Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival

Carlo Sorrentino, Zhinan Yin, Stefania Ciummo, Paola Lanuti, Li Fan Lu, Marco Marchisio, Matteo Bellone, Emma Di Carlo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number201
JournalJournal for ImmunoTherapy of Cancer
Volume7
Issue number1
DOIs
Publication statusPublished - Jul 31 2019

Keywords

  • Immunohistochemistry
  • Interleukin-30
  • Prostate Cancer Stem-Like Cells
  • Treg cells
  • Tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival'. Together they form a unique fingerprint.

Cite this