Dual Prognostic Significance of Tumor Associated Macrophages in Human Pancreatic Adenocarcinoma Treated or not with Chemotherapy

Tumor-associated macrophages (TAMs) play key roles in tumor progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer. In a large retrospective cohort study involving 110 pancreatic ductal adenocarcinoma (PDAC) patients, we addressed the clinical relevance of TAMs and the mechanisms regulating their function in PDAC. Density of CD68-TAM immune reactive area (IRA%) was evaluated at the tumor-stroma interface. Prognostic relevance was evaluated in relation to post-surgical adjuvant chemotherapy treatment (CTX). The synergism of chemotherapy and TAMs was dissected in vitro. In human PDAC, TAMs predominantly exhibited an immunosuppressive profile, characterized by expression of scavenger receptors (CD206, CD163) and production of IL-10. Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumor prognostic significance. High density of TAMs at the tumor margin positively dictated prognostic responsiveness to CTX independently of T cell density. Accordingly, in vitro, Gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression program. In human PDAC patients, neoadjuvant CTX was associated to a decreased density of CD206-TAMs at the tumor margin. Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX directly reeducates TAMs to an anti-tumor phenotype. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide basis for novel strategies aimed at reeducating macrophages in the context of chemotherapy treatment.