Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS
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PROVIDER: PRJNA507717 | ENA |
REPOSITORIES: ENA
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Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
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2023-06-16 | MSV000092193 | MassIVE
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:T-cell/histiocyte rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of diffuse large B cell lymphoma (DLBCL) that usually affects young to middle-aged patients, with disseminated disease at presentation. The tumor microenvironment (TME) plays a key role in THRLBCL, due to its peculiar cellular composition (less than 10% neoplastic B-cells interspersed in a cytotoxic T-cell/histiocyte rich background). A significant percentage of THRLBCL is refractory to RCHOP-based regimens and to CAR-T therapy; thus, the development of a specific therapeutic approach for these patients still represents an unmet clinical need. To better understand the interaction of immune cells in THRLBCL TME and identify more promising therapeutic strategies, we compared the immune gene expression profiles of 12 THRLBCL and 10 DLBCL samples, using the Nanostring PanCancer Immune Profiling panel. Gene co-expression network analysis identified the predominant role of the PD-1/PD-L1 axis in the modulation of the immune response. Furthermore, the PD-1/PD-L1 activation was flanked by the overexpression of as many as 48 genes related to the functional exhaustion of T-cells. Globally, THRLBCL TME was highly interferon-inflamed and severely exhausted. The immune gene profiling findings strongly candidate THRLBCL for anti-PD-1 therapy, but also allowed us to take a step forward in understanding THRLBCL TME. Of therapeutic relevance, we identified a subset of TCF1+ progenitor exhausted T-cells enriched in THRLBCL patients. This subset of TCF1+ exhausted T-cells correlates with good clinical response to immune checkpoint therapy and may improve prediction of anti-PD-1 response in THRLBCL patients.
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Project description:Blocking PD-1 can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. One potential advantage of this immunotherapy is durable protection if immune memory can be established. It is unclear, however, whether blocking PD-1 can reprogram TEX into effector (TEFF) or durable memory T cells (TMEM). Here, we found reinvigoration of TEX by PD-L1 blockade caused re-acquisition of some features of TEFF, but minimal memory development. We used microarray analysis to profile exhausted cells from anti-PD-L1 mice after two weeks of treatment to study if PD-L1 blockade caused re-acquistion of some feature of effector or memory cells.
2016-10-31 | GSE86796 | GEO
Project description:Upon PD-1 pathway blockade,the epigenetic landscape of exhausted cells was only minimally remodeled consistent with lineage commitment and re-exhaustion of these cells over time.
2016-10-31 | GSE86797 | GEO
Project description:CD8 T cells that respond to PD-1 blockade (during the early stage of infection) have enriched CD28 costimulation genes During the early stages of chronic infection PD-1 blockade is effective are rescuing exhausted CD8 T cells. However during the later stages of chronic infection PD-1 blockade is not able to induce a significant rescue of exhausted T cells. In order to understand the transcriptional basis of these difference we performed an RNA comparison. There is enrichment in several genes and pathways, and we hypothesize that these could be exploited for optimizing immune checkpoint therapies during the later stages of chronic infection.
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Project description:Alzheimer’s disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a PD-1 ligand, was found to have similar efficacy to that of PD-1 blocking in disease modification, in both animal models of AD and of tauopathy. Targeting PD-L1 in a tau-driven disease model resulted in increased immunomodulatory monocyte-derived macrophages within the brain parenchyma. Single cell RNA-seq revealed that the homing macrophages expressed unique scavenger molecules including macrophage scavenger receptor 1 (MSR1), which was shown here to be required for the effect of PD-L1 blockade in disease modification. Overall, our results demonstrate that immune checkpoint blockade targeting the PD-1/PD-L1 pathway leads to modification of common factors that go awry in AD and dementia, and thus can potentially provide an immunotherapy to help combat these diseases.
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Project description:Immune checkpoint blockade (ICB) has shown remarkable efficacy, but in only a minority of cancer patients, suggesting the need to develop additional treatment strategies.We integrated transcriptional profiles of treatment-naïve human tumors and functional CRISPR screens to identify glycometabolism genes with immunomodulatory effects. We identified MAN2A1, encoding an enzyme in N-glycan maturation, as a key immunomodulatory gene. Analyses of public immune checkpoint blockade trial data also suggested a synergy between MAN2A1 inhibition and anti-PD-L1 treatment. Loss of Man2a1 in cancer cells increased their sensitivity to T cell-mediated killing. Man2a1 knockout enhanced response to anti-PD-L1 treatment and facilitated higher cytotoxic T cell infiltration in tumors under anti-PD-L1 treatment. Furthermore, a pharmacological inhibitor of MAN2A1, swainsonine, synergized with anti-PD-L1 in syngeneic melanoma tumor model, whereas each treatment alone had little effect.
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