RT Journal Article
SR Electronic
T1 Targeting Interleukin(IL)-30/IL-27p28 signaling in cancer stem-like cells and host environment synergistically inhibits prostate cancer growth and improves survival
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 201
DO 10.1186/s40425-019-0668-z
VO 7
IS 1
A1 Carlo Sorrentino
A1 Zhinan Yin
A1 Stefania Ciummo
A1 Paola Lanuti
A1 Li-Fan Lu
A1 Marco Marchisio
A1 Matteo Bellone
A1 Emma Di Carlo
YR 2019
UL http://jitc.bmj.com/content/7/1/201.abstract
AB 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.Abbreviations:BCRBiochemical recurrenceCasp3Caspase-3CCLChemokine (C-C motif) ligandCSFColony-stimulating factorCXCLChemokine (C-X-C motif) ligandEIIa-p28f/fIL-27p28 conditional knockout mouse strainIDOIndoleamine 2,3-dioxygenaseIFNγInterferon gammaILInterleukinIL-30+/+tumorsPIN-SC or shPIN-SC tumors in WT miceIL-30-/-tumorsIL-30shPIN-SC tumors in IL-30KO miceIL-30+/-tumorsPIN-SC or shPIN-SC tumors in IL-30KO miceIL-30-/+tumorsIL-30shPIN-SC tumors in WT miceILKInfiltrating leukocytesKOKnockoutMDCsMyeloid derived cellsMTVMean tumor volumePCProstate cancerPCNAProliferating cell nuclear antigenPC-SLCsProstate Cancer Stem-Like CellsPIN-SCsProstatic intraepithelial neoplasia-derived stem-like cellsPTGS2Prostaglandin-endoperoxide synthase 2Sca-1Stem cells antigen-1shRNAShort hairpin RNATIA-1Cytotoxic granule-associated RNA binding proteinTMETumor microenvironmentTNFTumor necrosis factorTRAILTNF-related apoptosis-inducing ligandTregsT regulatory cellsTUNELTerminal deoxynucleotidyl transferase dUTP nick end labelingWTWild type