Interleukin-30/IL-27p28 shapes prostate cancer stem-like cell behavior and is critical for tumor onset and metastasization

Prostate cancer (PC) stem-like cells (PCSLCs) are believed to be responsible for PC onset and metastasis. Autocrine and microenvironmental signals dictate PCSLC behavior and patient outcome. In PC patients, interleukin(IL)-30/IL-27p28 has been linked with tumor progression, but the mechanisms underlying this link remain mostly elusive. Here we asked whether IL-30 may favor PC progression by conditioning PCSLCs and assessed the value of blocking IL-30 to suppress tumor growth. IL-30 was produced by PCSLCs in human and murine prostatic intraepithelial neoplasia and displayed significant autocrine and paracrine effects. PCSLC-derived IL-30 supported PCSLC viability, self-renewal and tumorigenicity, expression of inflammatory mediators and growth factors, tumor immune evasion and regulated chemokine and chemokine receptor genes, primarily via STAT1/STAT3 signaling. IL-30 overproduction by PCSLCs promoted tumor onset and development associated with increased proliferation, vascularization and myeloid cell recruitment. Furthermore, it promoted PCSLC dissemination to lymph nodes and bone marrow by upregulating the CXCR5/CXCL13 axis, and drove metastasis to lungs through the CXCR4/CXCL12 axis. These mechanisms were drastically hindered by IL-30 knockdown or knockout in PCSLCs. Collectively, these results mark IL-30 as a key driver of PCSLC behavior. Targeting IL-30 signaling may be a potential therapeutic strategy against PC progression and recurrence.