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

Classifying the Microenvironment of Mesothelioma

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

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

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

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

Delayed maturation of an IL-12–producing dendritic cell subset explains the early Th2 bias in neonatal immunity

Primary neonatal T cell responses comprise both T helper (Th) cell subsets, but Th1 cells express high levels of interleukin 13 receptor α1 (IL-13Rα1), which heterodimerizes with IL-4Rα. During secondary antigen challenge, Th2-produced IL-4 triggers the apoptosis of Th1 cells via IL-4Rα/IL-13Rα1, thus explaining the Th2 bias in neonates. We show that neonates acquire the ability to overcome the Th2 bias and generate Th1 responses starting 6 d after birth. This transition was caused by the developmental maturation of CD8α+CD4− dendritic cells (DCs), which were minimal in number during the first few days of birth and produced low levels of IL-12. This lack of IL-12 sustained the expression of IL-13Rα1 on Th1 cells. By day 6 after birth, however, a significant number of CD8α+CD4− DCs accumulated in the spleen and produced IL-12, which triggered the down-regulation of IL-13Rα1 expression on Th1 cells, thus protecting them against IL-4–driven apoptosis

Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation. Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs. Results: CD8+BTLA? TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA? T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR

Clinical and Environment Factors Impacting Malignant Pleural Mesothelioma Prognosis

View full abstracthttps://openworks.mdanderson.org/leading-edge/1012/thumbnail.jp

Shared Nearest Neighbors Approach and Interactive Browser for Network Analysis of a Comprehensive Non-Small-Cell Lung Cancer Data Set

View full abstracthttps://openworks.mdanderson.org/leading-edge/1000/thumbnail.jp