Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited treatment options. The abundant desmoplastic stroma and immune cells interspersed within it are hallmarks of this disease. Recent studies have identified a non-canonical CD8+ T-cell subtype, Tc17, which promotes autoimmunity and has been found in tumors.
According to a recent study in Gut, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal solid cancer with a low overall survival rate of around 9%. The cancer is characterized by an abundant desmoplastic stroma that consists of cancer-associated fibroblasts (CAFs) and immune cells, which create an inflammatory environment that supports cancer progression, heterogeneity, and drug resistance. CAFs are involved in the tumour microenvironment (TME) and produce factors that regulate cell infiltration and function.
Depending on the subtype, CAFs can either promote or inhibit PDAC progression. TGFβ produced by tumour cells, myeloid cells, and regulatory T cells drives myofibroblastic CAF differentiation.
In PDAC, IL-17A, which different lymphocyte populations can produce, induces the production of CXCL1, CXCL2, CXCL8, IL-6, and G-CSF, which promotes myeloid cell infiltration. IL-17A also supports early carcinogenesis, regulates PDAC stem cell features, promotes tumor growth, mediates resistance to checkpoint inhibitors, and modulates the CAF transcriptome. Tc17 cells, a non-cytotoxic subset of CD8+ T cells that produce IL-17A/F, have not been previously described in PDAC, but the data presented suggest they are a new pathogenic cell population in the pancreatic TME that accelerates PDAC growth.
The article discusses a study investigating the role of a specific type of CD8+ T cells, called Tc17, in promoting pancreatic ductal adenocarcinoma (PDAC) by inducing inflammatory cancer-associated fibroblasts (iCAF). The study found that Tc17 cells were in high numbers in PDAC patients, and they induced iCAF differentiation by the synergistic effects of IL-17A and TNF.
The co-culture of tumor cells with Tc17-iCAF resulted in increased proliferation and gene expression implicated in tumor growth. The study identified Tc17 as a novel protumorigenic CD8+ T-cell subtype that promoted PDAC progression through IL-17RA-dependent stroma modification.
Pancreatic ductal adenocarcinoma (PDAC) has an abundant desmoplastic stroma, accounting for up to 90% of the thetumorr mass, consisting of cancer-associated fibroblasts (CAFs) and infiltrating immune cells. In this microenvironment, reciprocal interactions between immune and non-immune cells occur, impacting tumorigenesis. Tumour-infiltrating Tc17 cells have been identifie,d and they skew IL-17RA+CAF towards an inflammatory phenotype via the synergism of IL-17A and TNF. Tc17-iCAF via secreted IL-6 directs TGF-β-dependent Tc17 differentiation, indicating an amplification loop.
Increased frequency of Tc17 cells correlated with tumor size and progressed stage, thereby indicating their disease-promoting function. Th17 cells, another subpopulation of IL-17A-producing cells, is associated with advanced tumor stage, but they fail to correlate with shorter patient survival and act as an independent prognostic marker for PDAC.
Besides Tc17 and Th17 cells, other cell populations might contribute to PDAC differently. Tc17 cells and their products, unlike other IL-17A-producing cells, can drive an iCAF-specific transcriptome, promoting atumor-promotingg function. Tc17 cells induce iCAF-marker genes via the synergism of IL-17A and TNF. The Tc17-iCAF boosts the growth of murine and humantumorss as compared with qPSC, CTL-CAF, or DKO-CAF in Rag1-/- and Foxn1nu/nu mice.
In addition to in vitro effects, Tc17 and IL-17A/F promote the iCAF phenotype and tumor growth in mouse orthotopic and subcutaneous models. IL-17RA expression by qPSC is required to sense Tc17 signals mediating iCAF differentiation and thereby promote tumor growth, as uncovered by reconstitution experiments in IL-17RA-deficient mice.
Overall this study has identified Tc17 as a novel protumorigenic CD8+ T-cell subtype in PDAC. Tc17 cells accelerate tumor growth via IL-17RA-dependent stroma modification, promoting PDAC progression and resulting in poor patient prognoses. Our findings demonstrate a crosstalk between Tc17 cells, fibroblasts, and tumor cells, highlighting the need for further research on potential targeted therapies to disrupt this interaction and improve PDAC treatment outcomes.
