ABSTRACT
Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be 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. 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 drove 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.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Animals , Mice , Humans , Pancreatic Neoplasms/metabolism , Macrophages/metabolism , Carcinoma, Pancreatic Ductal/metabolism , Immunotherapy , Cell Proliferation , Tumor Microenvironment , Cell Line, TumorABSTRACT
Tissue-engineered scaffolds have been identified as appropriate templates for bone regeneration, especially complex geometries seen in craniofacial defects. Here we describe the general fabrication and modification of hydrogels, cryogels, and electrospun scaffolds. These scaffolds offer a variety of templates for facilitating bone growth and regeneration in craniofacial applications.