The role of tumor-associated macrophages in pancreatic cancer

Abstract

[EMBARGOED UNTIL 8/1/2024] Due to the lack of early diagnosis and efficient therapy, it is projected that pancreatic cancer (PaC) will become the second leading cause of cancer-related death in the U.S. by 2030. Conventional therapies provide very limited benefit to human patients. Surgery, as a potential cure, is only available for a small proportion of patients. PaC is resistant to most therapies and has a dense desmoplastic stroma, and most patients die of distant metastasis. Tumor-associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and play essential roles in the regulation of tumor progression and immunity. In recent years, macrophage-targeted monotherapy or integrated therapies have been investigated in pre-clinical models. However, only limited success was obtained when these drugs or ideals translated into clinic trials. PaC is resistant to immune checkpoint therapy, but the underlying mechanisms are largely unknown. In this study, comparative analysis of single-cell RNA sequencing (scRNA-Seq) data and validated experiments demonstrated that more exhausted effector CD8+ T cells and increased M2-like TAMs with a reduced capacity of antigen presentation are detected in resistant Panc02-formed tumors versus responsive Panc02-H7-formed tumors. Our data highlight the correlation of tumor-induced imbalance of macrophages with the fate of tumor-resident effector CD8+ T cells and PaC response to [alpha]PD-1 immunotherapy. TAMs as a critical regulator of tumor immunity and immunotherapy contribute to PaC resistance to immune checkpoint blockade. Using scRNA-Seq, we identified TAMs as the main cells producing transforming growth factor-beta-induced protein (TGFBI, also known as [beta]ig-H3). Further in vitro and in vivo studies demonstrate that TGFBI as a macrophage (M[phi])-intrinsic and secreted factor promotes PaC tumor growth, programs M[phi], and impacts T cell activation and exhaustion. These exciting findings inspire us to perform further mechanistic studies and the potential of TGFBI and M[phi] as PaC therapeutic targets.