Macrophage proliferation machinery drives immunosuppression and tumor progression Chong Zuo1, Brett Knolhoff1, John Baer1, Jad Belle1, Christina Fu2, David DeNardo1,3 1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA 2Grinnell College, Grinnell, IA, 50112,USA 3 Alvin J. Siteman Comprehensive Cancer Center, St. Louis, MO 63110, USA Tumor associated macrophages (TAMs) are involved in many aspects of cancer development and are frequently negatively correlated with cancer patient outcomes. We have previously found that in pancreatic ductal adenocarcinoma (PDAC), a significant percentage of TAMs are highly proliferative. To better understand the impacts of macrophage proliferation on macrophage phenotypes, numbers and PDAC patient outcomes, we used parallel studies in human PDAC tissues and genetically engineered mouse models (GEMM) to model both PDAC and manipulate macrophage proliferation. First, we identified cancer-associated fibroblasts (CAFs), rather than cancer cells, as the primary drivers of macrophage proliferation through the production of macrophage colony-stimulating factor (M-CSF). We also observed that proliferating macrophages in single cell RNA sequencing data (ssRNAseq) from human and mouse tumors have enhanced inflammatory and immunosuppressive phenotypes. To examine whether limiting proliferation of TAMs would alter PDAC progression in vivo, we developed a GEMM to manipulate expression of the cell cycle inhibitor p21. Unexpectedly, expression of p21, while limiting macrophage proliferation, enforced macrophage immunosuppressive capacity and led to loss of T cell tumor control and increased tumor progression. In in vitro models and in vivo ssRNAseq data from mouse PDAC, we observed the expression level of p21 in macrophages is linked to elevated expression of both inflammatory and immunosuppressive cytokines. This observation also holds true in analyzing samples from human PDAC patient, stratification of TAMs by either proliferation or p21 expression identifies a subset of highly inflammatory TAMs. Finally, we have found that treatment with chemotherapy induces p21 expression in macrophages. Taken together, these data suggest that the macrophage proliferation machinery, including p21, is a critical regulator of immune suppression in PDAC tumors and that chemotherapy, while killing tumor cells, may ultimately enforce this myeloid driven immune suppression.
Washington University in Saint Louis
You must be logged in and own this session in order to