Pancreatic stellate cells and the interleukin family: Linking fibrosis and immunity to pancreatic ductal adenocarcinoma (Review)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive form of cancer with a low survival rate. A successful treatment strategy should not be limited to targeting cancer cells alone, but should adopt a more comprehensive approach, taking into account other influential factors. These include the extracellular matrix (ECM) and immune microenvironment, both of which are integral components of the tumor microenvironment. The present review describes the roles of pancreatic stellate cells, differentiated cancer‑associated fibroblasts and the interleukin family, either independently or in combination, in the progression of precursor lesions in pancreatic intraepithelial neoplasia and PDAC. These elements contribute to ECM deposition and immunosuppression in PDAC. Therapeutic strategies that integrate interleukin and/or stromal blockade for PDAC immunomodulation and fibrogenesis have yielded inconsistent results. A deeper comprehension of the intricate interplay between fibrosis, and immune responses could pave the way for more effective treatment targets, by elucidating the mechanisms and causes of ECM fibrosis during PDAC progression.

Keywords: cancer‑associated fibroblast; interleukin; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; pancreatic stellate cell.

Figure 1.

Changes in the TME of pancreatic cancer progression. (A) Pre-invasive PanIN lesions develop from normal ductal epithelia, through PanIN stages 1, 2 and 3, to stage 3 development process. (B) Quiescence and differentiation of aPSC. qPSC markers include Nrxn2, Prelp, Serping1, ADIRF and FABP4, myCAF markers include Acta2, Tagln, Tpm2, Col12a1 and Tpm1, iCAF markers include IL-6 and Pdgfra, and apCAF markers include H2-Ab1, CD74, Hla-dra and slpi. (C) Components of the PDAC tumor microenvironment. qPSC, quiescent pancreatic stellate cell; aPSC, activated pancreatic stellate cell; Mø, macrophages; M2 ø, type 2 macrophages; MDSC, myeloid-derived suppressor cell; Treg, regulatory cell; Nrxn2, neurexin 2; Prelp, proline/arginine-rich end leucine-rich repeat protein; Serping1, serpin peptidase inhibitor, clade G (C1 inhibitor), member 1; ADIRF, adipogenesis regulatory factor; FABP4, fatty acid binding protein 4; Acta2, actin α2, smooth muscle; Tagln, transgelin; Tpm1/2, tropomyosin 1/2; Col12a1, collagen type XII α1; Pdgfra, platelet-derived growth factor receptor α; H2-Ab1, histocompatibility 2, class II antigen A, β1; CD74, leukocyte differentiation antigen 74; Hla-dra, human leukocyte antigen-dr α; slpi, secretory leukocyte protease inhibitor; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma.

Figure 2.

Crosstalk between pancreatic stellate cells and the IL-1 family, IL-6 family, IL-10 family and IL-17A of cytokines in PDAC. aPSC, activated pancreatic stellate cell; NK, natural killer; ILC, innate lymphoid cell; Th1/2, helper T1/2; CD4⁺ T cell, CD4⁺ T helper cell; CD8⁺ T cell, CD8⁺ T helper cell; IL-18Rα, interleukin-18 receptor α; IL-18Rβ, interleukin-18 receptor β; IL-1RAcP, interleukin-1 receptor accessory protein; Tyk2, tyrosine kinase 2; PDAC, pancreatic ductal adenocarcinoma.

Figure 3.

Survival of IL-1 family, IL-6 family and IL-10 family cytokines in patients with pancreatic ductal adenocarcinoma. Overall survival for patients with high (top quartile) and low (bottom quartile) level expression of (A) IL-1, (B) IL-6, (C) IL-10, (D) IL-11, (E) IL-18, (F) IL-18BP, (G) IL-20 and (H) IL-33. HR, hazard ratio.