Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE153262 | GEO | 2020/09/08
REPOSITORIES: GEO
Similar Datasets
Project description:While immune signaling has emerged as a defining feature of the glioma microenvironment, local selection of responding T cells and their anti-tumor potential as a population are difficult to measure directly in patients. High-throughput sequencing of T cell receptor repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. Here, we define new immunophenotypes in glioma based on TCRseq and RNA-Seq of tumor tissue, non-neoplastic brain tissue, and peripheral blood from patients. Using information theory, we characterize antigen-driven selection in glioma and its relationship with the expression of distinct immune-functional pathways in the tumor microenvironment. Finally, we identify a strong relationship between usage of certain TCR in peripheral blood and the divergence of the infiltrating T cell population from the peripheral repertoire. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to anti-glioma vaccines and immunotherapy. We characterized the T cell receptor (TCR) repertoires of 11 high-grade glioma patients, three low-grade glioma patients, and thee non-glioma patients by TCRseq of brain-infiltrating T cells and matching peripheral blood. In addition, we obtained gene expression profiles from brain tissue of each patient by RNA-Seq. We additionally measured the TCR repertoires exclusively from peripheral blood of one additional non-glioma patient.
2016-05-18 | E-GEOD-79338 | biostudies-arrayexpress
Project description:The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS, and the presence of fully mature clonotypes at distance. In TLS+ tumors, IgG- and IgA-producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptotic malignant cells, suggestive of anti-tumor effector activity. Therapeutic responses and progression-free survival correlated with IgG-stained tumor cells in RCC patients treated with immune checkpoint inhibitors. Thus, intratumoral TLS sustains B cell maturation and antibody production that is associated with response to immunotherapy, potentially via direct anti-tumor effects.
2022-03-03 | GSE175540 | GEO
Project description:While immune signaling has emerged as a defining feature of the glioma microenvironment, local selection of responding T cells and their anti-tumor potential as a population are difficult to measure directly in patients. High-throughput sequencing of T cell receptor repertoires (TCRseq) provides a population-wide statistical description of how T cells respond to disease. Here, we define new immunophenotypes in glioma based on TCRseq and RNA-Seq of tumor tissue, non-neoplastic brain tissue, and peripheral blood from patients. Using information theory, we characterize antigen-driven selection in glioma and its relationship with the expression of distinct immune-functional pathways in the tumor microenvironment. Finally, we identify a strong relationship between usage of certain TCR in peripheral blood and the divergence of the infiltrating T cell population from the peripheral repertoire. We anticipate that these immunophenotypes will be foundational to monitoring and predicting response to anti-glioma vaccines and immunotherapy.
2016-05-18 | GSE79338 | GEO
Project description:Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 33 HA20 patients, we show that heterozygous TNFAIP3 loss skews immune repertoires towards lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas.
2023-07-28 | E-MTAB-12491 | biostudies-arrayexpress
Project description:Utilizing surgical and chemical skin sensory denervation methods, we show that afferent neurons support the growth of melanoma tumors in vivo. We demonstrate that sensory innervation limits the activation of effective anti-tumor immune response. Specifically, sensory ablation led to improved leukocyte recruitment and infiltration into tumors, decreased intratumoral lymphoid and myeloid immunosuppressive cells, and the activation of T effector cells within the TME. We found that cutaneous sensory nerves hinder the maturation of intratumoral high endothelial venules and the formation of mature tertriary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T cell clonality and expanded the B cell repertoire in the TME. Importantly, CD8a depletion prevented the denervation-dependent anti-tumor effects. Finally, we observed that the gene signatures associated with immune function and sensory innervation were inversely correlated in human primary cutaneous melanomas, and the latter was a negative prognostic marker of the overall survival in the examined cohort. Our results suggest that tumor-associated sensory neurons negatively regulate the development of effective anti-tumor immune responses, thereby defining a novel target for therapeutic intervention in the cancer setting.
2023-02-20 | GSE193065 | GEO
Project description:In CRC, 1) to identify epigenetic changes at inter-tumor and intra-tumor level, and 2) to relate intra-tumor clonality to clinical, molecular and histopathologic parameters. From 79 FFPE tumors, 3 different regions were macrodissected: invasive front (IF), digestive tract surface (DTS) and central bulk (CB). Clinical, molecular, and histopathologic parameters were stablished. Epigenetic analysis was performed using Infinium 450K beadchip (Illumina) and R statistics. Intra-tumor regions clustered together by patient. The biggest epigenetic changes were in IF vs DTS/CB. By patient, the most often divergent region was IF (49.4%) comparing with DTS and CB (25.3% in both). It did not correlate with histopathologic, molecular and clinical parameters.Epigenetic clonality is higher at intra-tumor level. The highest changes are observed in IF vs DTS/CB. No association with histopathologic, molecular, and clinical characteristics was found. SNP characterization of 9 patients of teh discovery cohort were hibridized on Infinium HumanOncoArray-500 v1 beadchip, to asses the genetic clonality of the samples among the three intratumoral regions studied.
2016-08-16 | GSE81362 | GEO
Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.
2024-02-14 | GSE241871 | GEO
Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.
2024-02-14 | GSE255448 | GEO
Project description:Mathematical modeling of regulatory T cell effects on renal cell carcinoma treatment
Lisette dePillis 1, , Trevor Caldwell 2, , Elizabeth Sarapata 2, and Heather Williams 2,
1.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
2.
Harvey Mudd College, Claremont, CA 91711, United States, United States, United States
Abstract
We present a mathematical model to study the effects of the regulatory T cells (Treg) on Renal Cell Carcinoma (RCC) treatment with sunitinib. The drug sunitinib inhibits the natural self-regulation of the immune system, allowing the effector components of the immune system to function for longer periods of time. This mathematical model builds upon our non-linear ODE model by de Pillis et al. (2009) [13] to incorporate sunitinib treatment, regulatory T cell dynamics, and RCC-specific parameters. The model also elucidates the roles of certain RCC-specific parameters in determining key differences between in silico patients whose immune profiles allowed them to respond well to sunitinib treatment, and those whose profiles did not.
Simulations from our model are able to produce results that reflect clinical outcomes to sunitinib treatment such as: (1) sunitinib treatments following standard protocols led to improved tumor control (over no treatment) in about 40% of patients; (2) sunitinib treatments at double the standard dose led to a greater response rate in about 15% the patient population; (3) simulations of patient response indicated improved responses to sunitinib treatment when the patient's immune strength scaling and the immune system strength coefficients parameters were low, allowing for a slightly stronger natural immune response.
Keywords: Renal cell carcinoma, mathematical modeling., sunitinib, immune system, regulatory T cells.
2020-01-06 | BIOMD0000000908 | BioModels
Project description:Recent advancements in microfluidics and high-throughput sequencing technologies have enabled recovery of paired heavy- and light- chain of immunoglobulins (Ig) and VDJ- and VJ- chains of T cell receptors (TCR) from thousands of single cells simultaneously. Due to the complexity of these polyclonal receptors, for many species single-cell immune repertoire sequencing assays are not yet commercially available. Rhesus macaques are one of the most well-studied model organisms of the human adaptive immune response; application of these new immune repertoire sequencing assays is highly relevant to vaccine and infectious disease studies. Here we use custom designed primers to target and enrich for every known Ig and TCR chain and isotype in the rhesus macaque animal model. We sequenced more than 110,000 cell barcodes from rhesus macaque repertoires using PBMC, splenocyte, and FACS-sorted T and B cell. We were able to recover every Ig and TCR isotype, measure clonal expansion in proliferating T cells, and pair repertoires with gene expression profiles of single cells. Our results establish the ability to perform single-cell based immune repertoire analysis in rhesus macaque.
2021-11-18 | GSE179722 | GEO