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The gastrointestinal tract represents one of the largest body surfaces that is exposed to the outside world. It is the only mucosal surface that is required to simultaneously recognize and defend against pathogens, while allowing nutrients containing foreign antigens to be tolerated and absorbed. It differentiates between these foreign substances through a complex system of pattern recognition receptors expressed on the surface of the intestinal epithelial cells as well as the underlying immune cells. These immune cells actively sample and evaluate microbes and other particles that pass through the lumen of the gut. This local sensing system is part of a broader distributed signaling system that is connected to the rest of the body through the enteric nervous system, the immune system, and the metabolic system. While local tissue homeostasis is maintained by commensal bacteria that colonize the gut, colonization itself may not be required for the activation of distributed signaling networks that can result in modulation of peripheral inflammation. Herein, we describe the ability of a gut-restricted strain of commensal bacteria to drive systemic anti-inflammatory effects in a manner that does not rely upon its ability to colonize the gastrointestinal tract or alter the mucosal microbiome. Orally administered EDP1867, a gamma-irradiated strain of Veillonella parvula , rapidly transits through the murine gut without colonization or alteration of the background microbiome flora. In murine models of inflammatory disease including delayed-type hypersensitivity (DTH), atopic dermatitis, psoriasis, and experimental autoimmune encephalomyelitis (EAE), treatment with EDP1867 resulted in significant reduction in inflammation and immunopathology.  Ex vivo  cytokine analyses revealed that EDP1867 treatment diminished production of pro-inflammatory cytokines involved in inflammatory cascades. Furthermore, blockade of lymphocyte migration to the gut-associated lymphoid tissues impaired the ability of EDP1867 to resolve peripheral inflammation, supporting the hypothesis that circulating immune cells are responsible for promulgating the signals from the gut to peripheral tissues. Finally, we show that adoptively transferred T cells from EDP1867-treated mice inhibit inflammation induced in recipient mice. These results demonstrate that an orally-delivered, non-viable strain of commensal bacteria can mediate potent anti-inflammatory effects in peripheral tissues through transient occupancy of the gastrointestinal tract, and support the development of non-living bacterial strains for therapeutic applications.

Successful treatment of melanoma patients with checkpoint inhibitors (CPI) has reinforced the importance of T cells in anti-tumor efficacy. Despite significant progress, CPI therapy is effective in only 40-50% of treated subjects, with substantial toxicity. As a result, it is imperative to understand the profile of T cell responses to tumor antigens, to determine if patterns of responsiveness can be identified for those subjects who respond to immunotherapy. ATLASTM is a T cell antigen discovery platform in which putative antigens are expressed as individual clones that can be processed by any subject's antigen presenting cells and presented as peptide epitopes in the context of their own MHC class I or II molecules. If autologous CD4+ or CD8+ T cells are added that are specific for a given clone in a given well, a readout of activation can be measured. We hypothesized that the ATLAS™ technology could be applied to characterize and profile the T cell responses to tumor-associated antigens (TAA) of diverse human subjects undergoing CPI therapy. As a proof of concept, an expression library containing 23 full-length melanoma TAA was constructed and used to interrogate memory CD4+ and CD8+ T cell responses from of a cohort of melanoma patients who have undergone treatment with pembrolizumab. All 23 TAA were cloned and sequence verified; 96% and 91% were successfully expressed in the CD4-specific and CD8-specific library, respectively. Peripheral blood mononuclear cells (PBMC) were collected from ten patients who had undergone immunotherapy with pembrolizumab; CD4+ and CD8+ T cells were sorted and non-specifically expanded, and monocytes differentiated into dendritic cells (MDDC) in vitro. PBMC yields were comparable to historical assay data with the exception of lower viability of MDDC. Memory T cell responses to TAA were detectable and this study suggests that T cell responses to TAA can be measured in multiple, HLA-diverse subjects during CPI therapy, without the need to derive cell lines or use predictive algorithms. Work is currently underway to increase both the number of antigens and participants evaluated. Analyses will include the frequency and breadth of responses and the relationship between CD4+ and CD8+ T cell responses in subjects who benefit from CPI therapy compared with those who do not. This work has implications for both patient stratification and identification of novel immunotherapies.