Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE144469 | GEO | 2020/06/29
REPOSITORIES: GEO
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Project description:Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsM interact with T-cells in suppressing proliferation as well as cytokine release of CD8+ and especially CD4+ T-cells in vitro, and that they support generation of Foxp3+ cells. We therefore tested their immunosuppressive potential in CD4+ T-cell-induced colitis in vivo. We found that injection of GCsM into mice with already established severe colitis abolishes the inflammation and results in significant clinical improvement within a few days. T-cells recovered from GCsM-treated mice reveal reduced secretion of pro-inflammatory cytokines IFN-M-oM-^AM-' or IL-17. Furthermore, accumulation of clusters of Foxp3+ CD4+ T-cells were detectable at local sites of inflammation in their colon. Thus, GCsM are able to modify T-cell responses in vitro and in vivo and are able to down-regulate and clinically cure an established severe T-cell mediated colitis. Bone marrow derived monocytes where cultured 16 h with media containing M-CSF (control monocytes) or media containing M-CSF and dexamethasone (GCsM). In three independent experiments, total RNA from GCsM and control monocytes was isolated and processed for microarray hybridization.
2014-09-02 | E-GEOD-54778 | biostudies-arrayexpress
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100808 | GEO
Project description:Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.
2017-08-10 | GSE100807 | GEO
Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253721 | GEO
Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253720 | GEO
Project description:Checkpoint inhibitor colitis (CPI colitis) is a frequent immune-related adverse event resulting from cancer immunotherapy that is currently treated with empiric immunosuppression such as corticosteroids. A greater understanding of the pathogenesis of CPI colitis in the steroid-refractory setting is required to develop better colitis interventions targeted to each patient. Using paired colon biopsies and blood from steroid-experienced patients with endoscopically confirmed CPI colitis, combined with control patients, we performed multiplexed single-cell transcriptomics (scRNA/TCRseq) and proteomics (CITEseq, CyTOF) to identify contributing immune and non-immune populations. In CPI colitis patient biopsies compared to healthy controls, we found enrichment of resident memory (RM) T cells in both the CD8+ and unexpectedly the CD4+ compartments, as well as cytotoxic CD8+ T cells. These 3 populations expressed exact matching TCR, suggesting that CD4+ RM and CD8+ RM T cells are clonal progenitors that give rise to tissue-destructive cytotoxic effectors. Unbiased CyTOF and confirmatory scRNAseq and CITEseq analysis identifies specific mobilized subpopulations of both cytotoxic CD8+ and CD4+ RM cells that express both activation markers CD38 and HLA-DR, underscoring their pathogenic potential. CPI colitis induces global upregulation of interferon signaling and antigen presentation, as well as epithelial-specific dysregulation of homeostatic pathways (aquaporin/solute transporters) which is shared with ulcerative colitis. However, distinct from ulcerative colitis, CPI colitis involves specific alterations in stromal cell metabolic (NAD+, tryptophan) or extracellular signaling (BMP) pathways that directly impact epithelial cell survival, arguing for distinct therapeutic targeting. Finally, endothelial cells in CPI colitis demonstrate enrichment of the integrin 47 ligand MADCAM-1 (which is targeted by anti-47 antibody vedolizumab to treat colitis). This ligand is enriched in CPI colitis patients who received TNF blockade and anti-CTLA-4, identifying subsets of patients who may be more responsive to vedolizumab treatment. This work identifies putative pathogenic resident memory and cytotoxic T cells, and non-immune stromal and endothelial populations, whose properties may nominate subsets of CPI colitis patients amenable to distinct targeting strategies.
2024-03-20 | GSE253719 | GEO
Project description:Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsM interact with T-cells in suppressing proliferation as well as cytokine release of CD8+ and especially CD4+ T-cells in vitro, and that they support generation of Foxp3+ cells. We therefore tested their immunosuppressive potential in CD4+ T-cell-induced colitis in vivo. We found that injection of GCsM into mice with already established severe colitis abolishes the inflammation and results in significant clinical improvement within a few days. T-cells recovered from GCsM-treated mice reveal reduced secretion of pro-inflammatory cytokines IFN- or IL-17. Furthermore, accumulation of clusters of Foxp3+ CD4+ T-cells were detectable at local sites of inflammation in their colon. Thus, GCsM are able to modify T-cell responses in vitro and in vivo and are able to down-regulate and clinically cure an established severe T-cell mediated colitis.
2014-09-02 | GSE54778 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
Project description:All healthy individuals have autoreactive T cells in their peripheral T cell pool, but peripheral tolerance mechanisms prevent these T cells from causing autoimmunity. Two primary mechanisms of peripheral tolerance are T cell anergy and clonal deletion, which occur after tolerogenic priming of T cells by dendritic cells (DCs). Induction of anergy and deletion are impaired in the absence of checkpoint receptors (like PD-1), but, once established, they are not reversed by blockade of checkpoint receptors. Thus, the occurrence of immune-related Adverse Events (irAEs) in up to 70% of patients treated with checkpoint inhibitor (CPI) immunotherapy has raised questions about how checkpoint receptors are functioning to maintain peripheral tolerance of autoreactive T cells under homeostatic conditions. To address this, we developed a novel mouse model for studying peripheral T cell tolerance in the skin in which the development of localized autoimmune-like pathology was dependent on skin-infiltrating CD8 T cells following skin-specific expression of T cell antigens (Ags) and administration of PD-1 blocking antibodies. Interestingly, Ag-specific CD8 T cells were found to infiltrate Ag-expressing skin even in the absence of PD-1 blockade, however they did not cause disease and in fact co-existed with the skin cells expressing their cognate Ag. At the protein level, non-pathogenic skin-infiltrating CD8 T cells produced lower amounts of many T cell effector proteins compared to their pathogenic counterparts, explaining the lack of cutaneous pathology, but non-pathogenic T cells were functional because they remodeled the local myeloid cell compartment. Moreover, and unlike in other models of tolerance, non-pathogenic and pathogenic skin-infiltrating CD8 T cells were nearly identical at the transcriptional level, indicating that both T cell populations were differentiating towards the same effector state. In this context, checkpoint receptors prevented the majority of the non-pathogenic CD8 T cells from reaching their terminal, fully effector and pathogenic state, thus maintaining tolerance in the skin. Finally, analysis of skin biopsies from two patients with cutaneous lichenoid irAEs showed presence of clonally expanded effector CD8 T cells with comparable transcriptional profiles in both lesional and non-lesional skin. Thus, our data are in line with a model of peripheral T cell tolerance where PD-1 allows peripheral Ag-specific effector CD8 T cells to co-exist in a tissue where their cognate Ag is expressed without causing pathology and provide a mechanism for the development of cutaneous lichenoid irAEs upon administration of CPI immunotherapy.
2023-05-27 | GSE228586 | GEO
Project description:An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1? TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
2019-01-16 | GSE122969 | GEO