GSE203026
Macrophage proliferation machinery leads to PDAC progression, but susceptibility to innate immunotherapy.
Tumor-associated macrophages (TAMs) are involved in many aspects of cancer progression and correlated with poor clinical outcomes in many cancer types, including pancreatic ductal adenocarcinomas (PDACs). Previous studies have shown that TAMs can populate PDAC tumors not only by monocyte recruitment but also by local proliferation. However, the impact local proliferation might have on macrhopage phenotype and cancer progression is unknown.  Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro system to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes, independent of their proliferative status. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also drive response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy.  Overall design: Examination of macrophage subsets in steady-state and PDAC tissue and after chemotherapy treatments