Abstract
Simple SummaryThe immunosuppressive microenvironment is closely related to the poor prognosis of patients with PDAC. Tfh cells play an anti-tumor function in various malignant solid tumors; however, the role of Tfh cells in PDAC has not been determined. In this study, we aimed to explore the function of Tfh cells in PDAC, and revealed a novel immunosuppressive mechanism mediated by Tfh cells. Tfh cells promoted the formation of an immunoactive tumor microenvironment by secreting CXCL13 and IL-21, and the high infiltration of Tfh cells correlated with better patient prognosis. However, the anti-tumor function of Tfh cells was inhibited by the PD-L1/PD-1 signaling pathway. Neoadjuvant chemotherapy could further reverse the function of Tfh cells. Our results provided new strategies to remodel the immunoactive tumor microenvironment of PDAC.Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a threat to human life, being a highly invasive and metastatic malignancy [1]
Tumor-Infiltrating Tfh Cells Are Beneficial for the Prognosis of Patients with pancreatic ductal adenocarcinoma (PDAC)
We tested other characteristic molecules related to Tfh cells such as ICOS, Bcl6, CXCL13, and interleukin 21 (IL-21) (Figure 1D)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a threat to human life, being a highly invasive and metastatic malignancy [1]. PDAC is a typical “cold” tumor, characterized by an immunosuppressive microenvironment [2,3]. Previous studies have revealed that the absence and low activation of CD8+ T cells induced by the matrix composition, especially myeloid cell infiltration, contribute to the immunosuppressive microenvironment [4,5,6,7], indicating the significant roles of T cells in the PDAC immune microenvironment. The anti-tumor role of B cells in establishing the immune response in PDAC has come to light recent years [8,9,10,11]; the precise regulatory mechanisms remain unexplored. We aimed to investigate a novel follicular helper T cells (Tfh cells)-mediated mechanism of immunosuppression in PDAC
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