Emerging roles for the IL-6 family of cytokines in pancreatic cancer

Abstract

Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.

Therapeutic targeting of STAT3 pathways in pancreatic adenocarcinoma: A systematic review of clinical and preclinical literature

“…The TME plays an important role in tumorigenesis and chemoresistance by close interaction with tumor cells. Furthermore, TME has been shown to be highly immunosuppressive, promoting immune evasion, hence sustaining tumor progression [18][19][20]. Immunotherapy, so far, has not demonstrated substantial clinical improvement as single agent in the treatment of PDAC [5].…”

“…Therefore, strategies simultaneously targeting PDAC tumor cells as well as different immune checkpoints might be needed. The interactions of PDAC tumor cells and different cells within the TME such as CAFs, MDSCs, TAMs, are mediated through GP130/JAK/STAT3 pathway [11,[17][18][19][20]68]. STAT3 inhibition might thus have consequences in shaping TME towards anti-tumor phenotype by acting on both immune and tumor cells [18][19][20].…”

“…The interactions of PDAC tumor cells and different cells within the TME such as CAFs, MDSCs, TAMs, are mediated through GP130/JAK/STAT3 pathway [11,[17][18][19][20]68]. STAT3 inhibition might thus have consequences in shaping TME towards anti-tumor phenotype by acting on both immune and tumor cells [18][19][20]. In combination with chemotherapeutic agents and immunotherapy, it might significantly increase therapeutic efficacy in the treatment of PDAC.…”

“…Interactions between different cells within the TME are mediated through signaling molecules such as STAT3 activation via IL-6-type cytokines. For instance, PDAC tumor cells can stimulate immune cells to secrete IL-6-type cytokines, supporting the development of immunosuppressive TAMs and MDSCs as well as the activation of PSCs and CAFs, which in turn induce the secretion of inflammatory cytokines through positive feedback loops [11,[17][18][19][20][21][22]. Thus, STAT3 activation drives immune cells towards immunosuppressive phenotype by inhibiting regulatory T-cells, which in turn sustains tumor immune evasion.…”

Missing links — epigenetic regulators of the pancreatic cancer–associated inflammation

“…This is of particular relevance since chronic but ineffective inflammation is considered a cornerstone of pancreatic oncogenesis. The first step in this process is catalyzed by epithelial cells, pancreatic stellate cells (PSCs), and CAFs which work in concert to create a dense desmoplastic stroma and a tumor milieu increasingly rich in inflammatory cytokines [24]. Subsequently recruited immune cells are largely skewed toward an immunosuppressive phenotype and provide further support for cancer growth.…”