While we have focused on transcription factors (TFs) in the development of mononuclear phagocytes, especially dendritic cells, this time I will present our new findings regarding tumor-associated macrophages in pancreatic ductal adenocarcinoma (PDAC).
PDAC remains one of the most intractable cancers with an extremely poor prognosis. Â Specifically, an abundance of immunosuppressive TAM subsets is strongly associated with poor outcomes across various cancers, including PDAC. Consequently, reprogramming TAM phenotypes has emerged as a promising therapeutic strategy.
Recently, we identified a key TF highly expressed in immunosuppressive TAMs in both human and mouse PDAC. Myeloid-specific deletion of this TF in PDAC mouse models markedly inhibited tumor progression. TAMs lacking this TF acquired anti-tumor properties, enhancing effector functions of intratumoral CD8+ T cells while attenuating their exhaustion. We also found that this TF induces an immune checkpoint gene, and myeloid-specific deletion of this gene similarly inhibited PDAC growth.
Supporting its clinical relevance, the TF–immune checkpoint axis correlated with exhausted CD8+ T cell signatures and poor prognosis in patients with PDAC. These findings demonstrate that this TF drives the tumor-promoting functions of TAMs, highlighting it as a potential therapeutic target for PDAC.