Mesenchymal Stromal Cells Equipped by IFNα Empower T Cells with Potent Anti-tumor Immunity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE184918 | GEO | 2021/10/31
REPOSITORIES: GEO
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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
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | MassIVE
Project description:Elucidating the mechanisms by which immune cells become dysfunctional in tumors is critical to developing next-generation immunotherapies. We profiled proteomes of cancer cells, monocyte/macrophages, CD4+ and CD8+ T cells, and NK cells isolated from tumors, liver, and blood of 48 patients with hepatocellular carcinoma. We found that tumor macrophages induce the sphingosine-1-phospate-degrading enzyme SGPL1, which dampened their inflammatory phenotype and anti-tumor function in vivo. We further discovered that the signaling scaffold protein AFAP1L2, typically only found in activated NK cells, is also upregulated in chronically stimulated CD8+ T cells in tumors. Ablation of AFAP1L2 in CD8+ T cells increased their viability upon repeated stimulation and enhanced their antitumor activity synergistically with PD-L1 blockade in mouse models. Our data revealed new targets for immunotherapy and provide a resource on immune cell proteomes in liver cancer (www.immunomics.ch/liver).
2023-04-19 | PXD040957 | Pride
Project description:Targeting checkpoint blockade to rescue exhausted regulatory T cells (Tregs) has become an essential immunotherapy strategy in treating cancer. Until now, the CD4+ Tregs and PD-1+CD8+ T cells were demonstrated to reduce immunogenic responses. In contrast, little is known about the PD-L1 graphic pattern and characteristics in CD8+ T cells. We performed two high-throughput analysis approaches on tumor-infiltrating CD8+ T cells in lung cancers. We discovered PD-L1+CD8+ T cells enriched in tumor lesions, localized with PD-1+CD8+ affected T cells, and owned regulatory functions. Moreover, tumor-derived IL-27 promoted the development of PD-L1+CD8+ T cells through STAT1/STAT3 signaling. Single-cell RNA sequencing data analysis further clarified the enrichment of PD-L1+CD8+ T cells related to the downregulation of adaptive immune response. Additionally, enrichment of this subset was correlated with poor survival of lung cancer patients. Our data collectively demonstrated that PD-L1+CD8+ T cells potentially become a prognostic biomarker in lung cancer.
2022-02-18 | GSE192591 | GEO
Project description:Currently approved inhibitors of the PD-1/PD-L1 pathway represent a major advance for the treatment of lung cancers, yet they are ineffective in a majority of patients due to lack of pre-existing T cell reactivity. Here we show that a TLR9 agonist delivered by inhalation is able to prime T cell responses against poorly immunogenic lung tumors and to complement the effects of PD-1 blockade. Treatment with inhaled TLR9 agonist causes profound remodeling in tumor-bearing lungs, leading to formation of tertiary lymphoid structures adjacent to the tumors, CD8+ T cell infiltration into the tumors, dendritic cell expansion and antibody production. Inhaled TLR9 agonist treatment increased the pool of functional PD-1lowT-bethigh effector CD8+ T in tumor-bearing lungs. We show by transcriptional profiling, that the effector CD8+ T cells generated by inhaled TLR9 agonist treatment are licensed by PD-1 blockade to become highly functional CTL, leading to a durable rejection of both lung tumors and tumor lesions outside the lungs. CD4+ T cells activated in response to inhaled TLR9 play a critical role in this process by controlling the proliferation, preventing exhaustion, and guiding the differentiation of optimally functional CTL. This study characterizes a strategy to apply localized TLR9 stimulation to a tumor type not accessible for direct injection, a strategy that may expand the therapeutic potential of PD-1 blockade in non-small cell lung cancer. the scope of this experiment was to profile the gene expression of effector CD8 T cells from tumor bearing lungs treated by different drug regimen.
2018-05-04 | GSE113987 | GEO
Project description:Interferon-alpha (IFNα) plays a ciritical role in immune regulation, especially in tumor microenvironment. Our previous study has demonstrated that IFNα promoted immunosuppression formation in head and neck squamous cell carcinoma. To explore the mechanism underlying IFNα-induced immunosuppression, long noncoding RNA (lncRNA) sequece was conduted. We identified a novel IFNα-induced upregulated lncRNA, lncMX1-215 in HNSCC. It was mainly located in cell nucleus. Ectopic expression of lncMX1-215 markedly inhibited IFNα-induced immunosuppression molecules, programmed cell death 1 ligand 1(PD-L1) and galectin-9 expression, and vice versa. Subsequently, histone deacetylase (HDAC) inhibitors promoted the expression of PD-L1 and galectin-9. There were binding sites of H3K27 acetylation on PD-L1 and galectin-9 promoters. Mechanically, we find that lncMX1-215 directly interacted with GCN5, a known H3K27 acetylase to interrupt its binding to H3K27 acetylation. Clinically, negative correlations between lncMX1-215 and PD-L1, galectin-9 were observed. Finally, overexpression of lncMX1-215 suppressed the proliferation and metastasis capacity in vitro and in vivo in HNSCC. Our results suggest that lncMX1-215 negatively regulates immunosuppression through interrupting GCN5/H3K27ac in HNSCC and provides novel insights into immune checkpoint blockade treatment.
2020-01-13 | GSE138147 | GEO
Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-? regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-? signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-? into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-? works as a tumor progressor through PD-L1 induction. The source of IFN-? in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-? and expression microarray analysis was performed, and probes showing significantly higher values in IFN-?-added group were termed “IFN-? signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-? signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-? in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-?-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment. Genome-wide transcriptional changes in human ovarian cancer tissue were observed in different tumor immunological microenvironment.
2014-03-04 | E-GEOD-55512 | biostudies-arrayexpress
Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.
2024-03-30 | GSE242860 | GEO
Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.
2015-04-12 | E-GEOD-61208 | biostudies-arrayexpress
Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
| phs001469 | dbGaP
Project description:Although understanding of T-cell exhaustion is widely based on mouse models, its analysis in cancer patients could provide clues indicating tumor sensitivity to immune checkpoint blockade (ICB). Data suggests a role for costimulatory pathways, particularly CD28, in exhausted T-cell responsiveness to PD-1/PD-L1 blockade. Here, we used single-cell transcriptomic, phenotypic, and functional approaches to dissect the relation between CD8+ T-cell exhaustion, CD28 costimulation, and tumor specificity in head and neck, cervical, and ovarian cancers. We found that memory tumor-specific CD8+ T cells, but not bystander cells, sequentially express immune checkpoints once they infiltrate tumors leading, in situ, to a functionally exhausted population. Exhausted T cells were nonetheless endowed with effector and tumor residency potential but exhibited loss of the costimulatory receptor CD28 in comparison to their circulating memory counterparts. Accordingly, PD-1 inhibition improved proliferation of circulating tumor-specific CD8 T cells and reversed functional exhaustion of specific T cells at tumor sites. In agreement with their tumor specificity, high infiltration of tumors by exhausted cells was predictive of response to therapy and survival in ICB-treated head and neck cancer patients. Our results showed that PD-1 blockade–mediated proliferation/reinvigoration of circulating memory T cells and local reversion of exhaustion occur concurrently to control tumors.
2020-05-01 | GSE148162 | GEO