Modulation of progenitor cells is involved in the development of chemotherapy triggered pro-metastatic monocytes 2568

Abstract Description Cell depletion induced by cytotoxic drugs could increase myelopoiesis to replenish depleted reserves. Our recent studies have demonstrated that the expanded myeloid cells due to myelopoiesis exhibit immunosuppressive and pro-metastatic phenotype. But the exact underlying mechanisms remain elusive. In this study, we hypothesize that the progenitor cells sense chemotherapy induced inflammation, which ultimately regulates monocyte development and phenotype changes via metabolic alterations. We show that multi-dose chemotherapy regimens induce an expansion of monocytes in the peripheral blood of breast cancer patients and lung tissues of tumor-bearing as well as tumor-free mice. This is associated with the increase of mitochondrial ROS (mtROS) production and mitochondrial oxidative phosphorylation (OXPHOS) in bone marrow Lin-Sca1+c-Kit+ cells (LSKs). Inhibition of mtROS abrogates high yield of monocytes from progenitor cells of chemotherapy treated mice. However, in vivo treatment with mtROS scavenger can’t reverse the chemotherapy induced pro-metastatic effect. Recent studies also highlight that beta-glucan in vivo treatment induces trained immunity through the education of myelopoiesis progenitors. Our data further reveal that β-glucan induced trained immunity remarkably reverses the pro-metastatic effect of chemotherapy. Together, these studies suggest that modulation of progenitor cells is responsible for the development of chemotherapy triggered pro-metastatic monocytes. Funding Sources NIH COBRE P20GM135004 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)