Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer

Abstract

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)-mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDACs) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 conventional DC (cDC2) development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from PDAC patients for changes in cDCs. We found circulating cDC2s and their progenitors were significantly decreased in the blood of PDAC patients, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in PDAC patents and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of PDAC patients showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.

An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer

“…Accordingly, most PDAC patients were found the remarkable lack of circulating DCs in peripheral blood, who were usually associated with worse survival outcomes. It suggested the significance of DCs in PDAC patients ( 91 , 92 ). In this regard, immense efforts have been put into the development of DC-based therapies for PDAC ( 16 , 93 ).…”

“…Dendritic cells (DCs) are professional antigen-presenting cells and initiate immune responses when fully activated. Numerous studies have reported that DC numbers and functions are significantly low in PDAC samples of patients, compared with other tumor types ( 91 , 92 ). Accordingly, most PDAC patients were found the remarkable lack of circulating DCs in peripheral blood, who were usually associated with worse survival outcomes.…”

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…Elevated levels of IL-6 in PDAC patients were found to negatively impact DC numbers and differentiation. This suggests that inflammatory cytokines suppress DCs, impairing antitumor immunity [ 127 ].…”

Dendritic cell subsets and implications for cancer immunotherapy

“…Moreover, certain cDC2s, upon acquiring an interferon-stimulating gene (ISG) activation state (ISG+ DCs), are able to MHC-dress with tumor-derived pMHC-1, stimulate CD8 T cells ex vivo, and drive tumor control even in the absence of cDC1 (75). Conversely, in the presence of high levels of IL-6 and PGE 2 , intratumoral cDC2s can also be driven toward a pro-tumor phenotype characterized by CD14 expression, upregulation of markers usually associated with tumor-associated macrophages (TAMs), and impaired antigen processing and presentation (76)(77)(78).…”