CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies.We examined CDK4/6 inhibition in mouse and human CD8 T cells during early stages of activation. Mice receiving tumor-specific CD8 T cells treated with CDK4/6 inhibitors displayed increased T cell persistence and immunologic memory. CDK4/6 inhibition upregulated Mxd4, a negative regulator of Myc, in both mouse and human CD8 T cells. Silencing of Mxd4 or Myc in mouse CD8 T cells demonstrated the importance of this axis for memory formation. We used single cell transcriptional profiling and TCR clonotype tracking to evaluate recently activated human CD8 T cells in breast cancer patients before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8 memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in cancer patients may augment long-term protective immunity.
Monocytes are circulatory precursor cells from myeloid origin that can develop into macrophages or dendritic cells upon migration from the blood stream to tissues. Both macrophages and dendritic cells are professional antigen-presenting cells. Monocytes and their macrophage and dendritic-cell progeny serve three main functions in the immune system. These are phagocytosis, antigen presentation, and cytokine production. THP-1 and U937 are (pro-) monocytic cell lines that can, also in vitro, be differentiated into either various types of macrophages or into dendritic cells.This chapter describes how to grow THP-1, resp. U937 cells, how to differentiate these into more specialised phenotypes such as various macrophage types or dendritic cells, how to read-out their responses to stimuli and it gives examples of how such cell lines have been used into studying the effects of food compounds.
Chagasic cardiomyopathy, resulting from infection with the parasite Trypanosoma cruzi, was discovered more than a century ago and remains an incurable disease. Due to the unique properties of mesenchymal stem cells (MSC) we hypothesized that these cells could have therapeutic potential for chagasic cardiomyopathy. Recently, our group pioneered use of nanoparticle-labeled MSC to correlate migration with its effect in an acute Chagas disease model. We expanded our investigation into a chronic model and performed more comprehensive assays. Infected mice were treated with nanoparticle labeled MSC and their migration was correlated with alterations in heart morphology, metalloproteinase activity, and expression of several proteins. The vast majority of labeled MSC migrated to liver, lungs and spleen whereas a small number of cells migrated to chagasic hearts. Magnetic resonance imaging (MRI) demonstrated that MSC therapy reduced heart dilatation. Additionally metalloproteinase activity was higher in heart and other organs of infected mice. Protein expression analyses revealed that connexin 43, laminin γ1, IL-10 and INF-γ were affected by the disease and recovered after cell therapy. Interestingly, MSC therapy led to upregulation of SDF-1 and c-kit in the hearts. The beneficial effect of MSC therapy in Chagas disease is likely due to an indirect action of the cells of the heart, rather than the incorporation of large numbers of stem cells into working myocardium.
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