Expansion, mobilization, and circulation of myeloid derived cells in mammary tumor bearing (TB) mice. (98.27)

Abstract

MDSCs are increased in the marrow (BM), lungs, liver, and tumors of TB hosts as compared to non-TB (NTB) mice. In vivo, BrdU labeling of leukocytes from 4T1 mammary TB mice revealed that MDSCs had an increased rate of proliferation in BM, spleen, lungs, and liver. MDSCs are observed in the highest frequency in the blood and spleen, suggesting hematopoietic progenitors mobilized from BM and proliferated following arrest. We assessed the biodistribution of circulating cells using CFSE-labeled spleen cells from TB mice, adoptively transferred to normal mice by iv injection and rapidly arrested in the lungs. In contrast, CFSE-labeled MDSCs injected into 4T1 TB mice transversed the lungs, briefly arrested in the liver, and were retained in BM and tumors. We posit that in 4T1 TB mice, the normal arrest in the pulmonary capillary bed is prevented by increased levels of nitric oxide from activated MDSCs resulting in capillary vasodilation and reduced arrest. In 4T1 TB mice, CD3+ T-cells are decreased, although the MFI of CFSE suggests proliferation. Annexin V staining revealed a high frequency of apoptotic CD3+ T-cells, associated with MDSC accumulation. In summary, MDSCs proliferate in lymphoid and parenchymal organs resulting in T-cell apoptosis possibly associated with activation-induced cell death. Further, although MDSCs proliferate in many organs, they rapidly circulate preferentially homing to the spleen and liver.