Targeting CD36-PPARβ signaling-mediated metabolic adaptation in intratumoral Tregs primes tumors for PD-1 blockade
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139325 | GEO | 2020/03/01
REPOSITORIES: GEO
Similar Datasets
Project description:Targeting CD36-PPARβ signaling-mediated metabolic adaptation in intratumoral Tregs primes tumors for PD-1 blockade
| PRJNA579319 | ENA
Project description:Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to inhibit the suppressive function of Tregs for cancer therapy, without impacting immune homeostasis. Identifying pathways that may distinguish tumor-restricted Tregs is important, yet the transcriptional programs that control intratumoral Treg gene expression, and that are distinct from Tregs in healthy tissues, remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC), in non-tumor tonsil tissues and in peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with non-tumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR/Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping and in vitro functional assays, corroborated the central role of BATF in limiting excessive activation and promoting the survival of human activated Tregs. Finally, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting potential opportunities for therapeutic intervention in cancer without impacting immune homeostasis.
2023-08-03 | GSE239750 | GEO
Project description:Copy number analyses of regionally separated intratumoral biopsies of prostate cancers. Intratumoral heterogeneity (ITH) leads to regional biases of the mutational landscape in a single tumor and may influence the single biopsy-based clinical diagnosis and treatment decision. To evaluate the extent of ITH in unifocal prostate cancers (PCAs) that had not been sought, we analyzed multiple regional biopsies from three PCAs using DNA copy number analyses. DNA copy number showed ITH including regional biases in the presentation of a well-known driver of TMPRSS2-ERG fusion. Our analyses identified a substantial level of genetic ITH in unifocal PCAs at the genomic levels, which should be taken into account for the curation of biomarkers in the clinical setting. Four intratumoral biopsies were obtained per tumor for three prostate cancers. Radical prostatectomy tissue from three patients with prostate cancers were obtained. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity). We selected four different areas for biopsy that were at least 5mm apart and were comprised of the most common Gleason pattern (the most common histologic patterns with minimal histologic differences). Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol.
2014-01-18 | E-GEOD-54185 | biostudies-arrayexpress
Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice
2019-04-02 | GSE126184 | GEO
Project description:Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency for the histone H3K27 methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a novel strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity.
2018-06-01 | GSE114298 | GEO
Project description:Copy number analyses of regionally separated biopsies from primary and metastatic lesions of five colorectal cancers A total of 35 intratumoral biopsies were obtained from primary and metastatic lesions of five colorectal cancers. Board-certified pathologists reviewed the hematoxylin&eosin stained sections and identified tumor-rich regions (> 80% purity) to ensure minimal contamination of normal tissues. We selected two to six different areas for biopsy that were at least 5mm apart in primary and distant metastatic lesions from a same patient. Copy number profiling was performed using Agilent 180K platform according to the manufacturer's protocol. The genomic DNA obtained from the adjacent normal tissues were used as reference genomic DNA for the tumor DNA of the corresponding patients.
2014-06-16 | E-GEOD-58512 | biostudies-arrayexpress
Project description:Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. Intratumoral administration is conceivably safer than systemic delivery and allows concentrate proinflammatory adjuvanticity in the tumor microenvironment and tumor-draining lymphoid tissue. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and that upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment of subcutaneous tumors derived from MC38, 4T1 and B16F10 with BO-112 leads to remarkable local disease control mediated by CD8+ T lymphocytes, as concluded from selective depletion experiments. Some degree of control of non-injected tumor lesions upon BO-112 intratumoral treatment was found in mice bearing bilateral B16OVA melanomas, that was enhanced when co-treated with systemic anti-CD137 and anti-PD-L1 immunomodulatory mAbs. More abundant CD8+ T lymphocytes were found in tumor-draining lymph nodes and in the tumor microenvironment following intratumoral treatment with BO-112. Enhanced numbers of tumor-specific CTLs recognizing melanosomal antigens and ovalbumin were readily detected among them. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098) and our results in mice suggest prominent anti-tumor local control through its proimmune effects. Intratumoral administration of BO-112, a nanoplexed form of PolyI:C, triggers an efficacious antitumor response in different tumor models as a consequence of proimmflamatory activity and its direct effects in tumor cells. BO-112 local administration induces direct tumor cell death by apoptosis, showing signs of immunogenic cell death, and a strong release of IFNα/β and other proinflammatory mediators. As a result, a tumor-specific CD8+ immune response is mounted or augmented to the point of controlling tumor progression both in the locally injected lesion and to some extent on distantly implanted tumor nodules
2019-05-15 | GSE116074 | GEO
Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m6A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m6 A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations.
2023-06-06 | GSE216960 | GEO
Project description:Regulatory T cells (Tregs) are a barrier to effective anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune homeostasis, Treg-restricted Nrp1 deletion in mice results in profound tumor resistant due to Treg functional fragility. Drivers of Treg fragility, the mechanistic basis of Nrp1 dependency, and the relevance of these processes for human cancer and immunotherapy remain unknown. NRP1 expression on human Tregs in melanoma and HNSCC was highly heterogeneous and correlated with prognosis. Using a mouse model of melanoma in which mutant Nrp1-deficient (Nrp1–/–) and wild type (WT) Tregs could be assessed in a competitive environment, we found that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which in turn drove the fragility of surrounding WT Tregs, boosting anti-tumor immunity and facilitating tumor clearance. We also show that IFNγ-induced Treg fragility is required for an effective response to PD1 immunotherapy, suggesting that cancer therapies promoting Treg fragility may be efficacious .
2017-05-22 | GSE97939 | GEO
Project description:Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. Intratumoral administration is conceivably safer than systemic delivery and allows concentrate proinflammatory adjuvanticity in the tumor microenvironment and tumor-draining lymphoid tissue. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and that upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment of subcutaneous tumors derived from MC38, 4T1 and B16F10 with BO-112 leads to remarkable local disease control mediated by CD8+ T lymphocytes, as concluded from selective depletion experiments. Some degree of control of non-injected tumor lesions upon BO-112 intratumoral treatment was found in mice bearing bilateral B16OVA melanomas, that was enhanced when co-treated with systemic anti-CD137 and anti-PD-L1 immunomodulatory mAbs. More abundant CD8+ T lymphocytes were found in tumor-draining lymph nodes and in the tumor microenvironment following intratumoral treatment with BO-112. Enhanced numbers of tumor-specific CTLs recognizing melanosomal antigens and ovalbumin were readily detected among them. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098) and our results in mice suggest prominent anti-tumor local control through its proimmune effects. To compare the in-vitro and in vivo transcriptional profile induced by BO-112, B16-OVA cell lines were incubated with BO-112 for 24h. BO-112 induces a specific transcriptional profile in B16-OVA cell cultures. Key immunoregulatory genes were found to be differentially expressed between BO-112 and Vehicle-incubated B16-OVA cells.
2019-05-15 | GSE116075 | GEO