Reversal of CNS autoimmunity by induction of oral tolerance to brain antigens mediated by antigen presenting cells of the lamina propria [abstract]

The phenomenon of oral tolerance is important for inducing non-reactivity to food borne antigens and commensal organisms by the immune system. In this study we have devised a method to induce tolerance to an auto-antigen, myelin oligodendrocyte glycoprotein (MOG), by oral administration of a chimeric immunoglobulin, Ig-MOG. Oral treatments with Ig-MOG ameliorated experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS)

Understanding T regulatory cell development in the thymus using both in vivo and in vitro models

Abstract only availableMultiple sclerosis (MS) is an autoimmune disease caused by autoreactive T cells attacking myelin sheath proteins in nerve fibers of the central nervous system resulting in paralysis and death. Conventional T cells (cytolytic and helper) initiate disease in MS, and T regulatory cells (Tregs) are conventional T cell suppressors. By studying the development of Tregs, a T cell suppressor, we can stop T cells from attacking myelin sheath proteins and prevent disease progression. All T cells develop in the thymus in three stages: double negative, double positive, and single positive. In the stage of my research's interest, the double positive stage, the T cell undergoes two educational phases, positive and negative selection. In positive selection, an antigen presenting cell (APC) presents a peptide to the T cell's T cell receptor (TCR). If the interaction between the peptide on the APC and TCR has a low affinity, then the T cell survives. However, if the affinity between the peptide and the TCR is high, the T cell dies via apoptosis. We hypothesize that Tregs require a strong affinity between the peptide and TCR to continue to the next educational phase. Interestingly, exposure high affinity peptides resulted in a decrease in Treg apoptosis both in vitro and in vivo. This observation is opposite to conventional T cell selection. We want to determine the ability of medium affinity peptide, PLP-Y, to prevent Treg apoptosis in vitro because ex vivo analysis shows PLP-Y does prevent Treg apoptosis in the thymus. Our results from in vitro experiments, however, did not show prevention of Treg death. Thus, it is likely more peptide is needed to provide the signal strength necessary for prevention of Treg death. Since many autoimmune diseases arise from poor Treg development, a better knowledge of the selection process may lead to potential therapies.Life Sciences Undergraduate Research Opportunity Progra

Spatial Modelling of the Tumor Microenvironment From Multiplex Immunofluorescence Images: Methods and Applications

Spatial modelling methods have gained prominence with developments in high throughput imaging platforms. Multiplex immunofluorescence (mIF) provides the scope to examine interactions between tumor and immune compartment at single cell resolution using a panel of antibodies that can be chosen based on the cancer type or the clinical interest of the study. The markers can be used to identify the phenotypes and to examine cellular interactions at global and local scales. Several translational studies rely on key understanding of the tumor microenvironment (TME) to identify drivers of immune response in immunotherapy based clinical trials. To improve the success of ongoing trials, a number of retrospective approaches can be adopted to understand differences in response, recurrence and progression by examining the patient\u27s TME from tissue samples obtained at baseline and at various time points along the treatment. The multiplex immunofluorescence (mIF) technique provides insight on patient specific cell populations and their relative spatial distribution as qualitative measures of a favorable treatment outcome. Spatial analysis of these images provides an understanding of the intratumoral heterogeneity and clustering among cell populations in the TME. A number of mathematical models, which establish clustering as a measure of deviation from complete spatial randomness, can be applied to the mIF images represented as spatial point patterns. These mathematical models, developed for landscape ecology and geographic information studies, can be applied to the TME after careful consideration of the tumor type (cold vs. hot) and the tumor immune landscape. The spatial modelling of mIF images can show observable engagement of T cells expressing immune checkpoint molecules and this can then be correlated with single-cell RNA sequencing data

Spatial Modelling of the Tumor Microenvironment From Multiplex Immunofluorescence Images: Methods and Applications

Spatial modelling methods have gained prominence with developments in high throughput imaging platforms. Multiplex immunofluorescence (mIF) provides the scope to examine interactions between tumor and immune compartment at single cell resolution using a panel of antibodies that can be chosen based on the cancer type or the clinical interest of the study. The markers can be used to identify the phenotypes and to examine cellular interactions at global and local scales. Several translational studies rely on key understanding of the tumor microenvironment (TME) to identify drivers of immune response in immunotherapy based clinical trials. To improve the success of ongoing trials, a number of retrospective approaches can be adopted to understand differences in response, recurrence and progression by examining the patient\u27s TME from tissue samples obtained at baseline and at various time points along the treatment. The multiplex immunofluorescence (mIF) technique provides insight on patient specific cell populations and their relative spatial distribution as qualitative measures of a favorable treatment outcome. Spatial analysis of these images provides an understanding of the intratumoral heterogeneity and clustering among cell populations in the TME. A number of mathematical models, which establish clustering as a measure of deviation from complete spatial randomness, can be applied to the mIF images represented as spatial point patterns. These mathematical models, developed for landscape ecology and geographic information studies, can be applied to the TME after careful consideration of the tumor type (cold vs. hot) and the tumor immune landscape. The spatial modelling of mIF images can show observable engagement of T cells expressing immune checkpoint molecules and this can then be correlated with single-cell RNA sequencing data

Classifying the Microenvironment of Mesothelioma

https://openworks.mdanderson.org/sumexp21/1204/thumbnail.jp

Differential Effects of Pancreatic Cancer-Derived Extracellular Vesicles Driving a Suppressive Environment

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs with or depleted of HA. Exposure of monocytes to sEVs resulted in unique phenotypic changes in HLA-DR, PD-L1, CD86 and CD64 expression, and cytokine secretion that was HA-independent except for IL-1β and MIP1β. In contrast, monocyte suppression of autologous T cell proliferation was reduced following exposure to HA-low sEVs. In addition, exposure of stellate cells to sEVs upregulated the secretion of various cytokines, including MMP-9, while removal of HA from PDAC-derived sEVs attenuated the secretion of MMP-9, demonstrating the role of sEV-associated HA in regulating expression of this pro-tumorigenic cytokine from stellate cells. This observation lends credence to the findings from the TCGA database that PDAC patients with high levels of enzymes in the HA synthesis pathway had worse survival rates compared with patients having low expression of these enzymes. PDAC-derived sEVs have an immune modulatory role affecting the activation state of monocyte subtypes. However, sEV-associated HA does not affect monocyte phenotype but alters cytokine secretion and suppression of autologous T cell proliferation and induces secretion of pro-tumorigenic factors by pancreatic stellate cells (PSC), as has been seen following the conversion of PSCs to cancer-associated fibroblasts (CAFs). Interruption of the hexosamine biosynthetic pathway, activated in PDAC producing the key substrate (UDP-GlcNAc) for HA synthesis, thus, represents a potential clinical interception strategy for PDAC patients. Findings warrant further investigations of underlying mechanisms involving larger sample cohorts

Spatial modelling of the tumor microenvironment from multiplex immunofluorescence images: methods and applications

Spatial modelling methods have gained prominence with developments in high throughput imaging platforms. Multiplex immunofluorescence (mIF) provides the scope to examine interactions between tumor and immune compartment at single cell resolution using a panel of antibodies that can be chosen based on the cancer type or the clinical interest of the study. The markers can be used to identify the phenotypes and to examine cellular interactions at global and local scales. Several translational studies rely on key understanding of the tumor microenvironment (TME) to identify drivers of immune response in immunotherapy based clinical trials. To improve the success of ongoing trials, a number of retrospective approaches can be adopted to understand differences in response, recurrence and progression by examining the patient’s TME from tissue samples obtained at baseline and at various time points along the treatment. The multiplex immunofluorescence (mIF) technique provides insight on patient specific cell populations and their relative spatial distribution as qualitative measures of a favorable treatment outcome. Spatial analysis of these images provides an understanding of the intratumoral heterogeneity and clustering among cell populations in the TME. A number of mathematical models, which establish clustering as a measure of deviation from complete spatial randomness, can be applied to the mIF images represented as spatial point patterns. These mathematical models, developed for landscape ecology and geographic information studies, can be applied to the TME after careful consideration of the tumor type (cold vs. hot) and the tumor immune landscape. The spatial modelling of mIF images can show observable engagement of T cells expressing immune checkpoint molecules and this can then be correlated with single-cell RNA sequencing data

The two faces of CD73 in tumor-infiltrating lymphocytes expanded from Liposarcoma

TMP-IL, Department of Translational Molecular Pathology Department of Sarcoma Medical Oncologyhttps://openworks.mdanderson.org/sumexp22/1056/thumbnail.jp

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues