Project description:The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell defective (BCD) mice, such as µ membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KO), have elevated anti-tumor immunity under specific-pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I interferon (IFN) signature in mucosal CD8+ T cells, resulting in upregulation of the type I IFN-inducible protein stem cells antigen-1 (Sca-1). Among CD8+ T cells, naïve cells predominantly circulate from the gut to periphery, and those that had migrated from the mLN to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1+ naïve subset is endowed with enhanced mitochondrial activity and anti-tumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8+ T cell compartment was revealed by single cell analysis and functional assays of CD8+ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates anti-tumor immunity.
Project description:This phase I pilot trial studies the side effects of cluster of differentiation 8 (CD8)+ T cells in treating patients with gastrointestinal tumors that have spread to other places in the body. Tumor cells and blood are used to help create an adoptive T cell therapy, such as CD8+ T cell therapy, that is individually designed for a patient and may help doctors learn more about genetic changes in the tumor. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CD8+ T cell therapy and pembrolizumab may work better in treating patients with gastrointestinal tumors.
Project description:To identify unique chromatin regions predicting the anti-tumor efficacy of Nrf2-deleted smart CD8+ T cell therapy, we performed an assay for transposase-accessible chromatin sequencing (ATAC-seq) using tumor-infiltrating CD8+ T cells from tumor-bearing mice transferred Nrf2-deficient CD8+ T cells. From the analysis of ATAC-seq data, we identified quantitatively distinct open regions of chromatin that distinguish Nrf2-deficient CD8+ T cells or WT CD8+ T cells.
Project description:Role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that, despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes down-regulated the expression of effector molecules, those located in the spleen appeared to be partly antigen-experienced and displayed a memory-like phenotype. Since ex vivo-reisolated self-reactive CD8+ T cells were very well capable to respond to the antigen in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung. We isolated antigen-specifc CD8+ T-cells from lungs and bronchial lymphnodes derived from chronic diseased mice (SPC-HAxCL4), healthy control mice (CL4) and acute influenza infected control mice (CL4+IAV) and perormed mRNA expression profiling of isolated CD8+ T cells. Each group represents a pool of at least n=4 animals. CD8+ T cell type comparison; lung disease state analysis
