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CITE-Seq analysis of intratumoral immune cells from YUMM1.7 melanoma treated with anti-PD-1 therapy.

ABSTRACT: Metastatic melanoma remains a disease difficult to treat, as 50% of the patients are resistant to immunotherapies or experience high toxicities. Investigations to identify underlying mechanisms focus on T cells or the immunosuppressive tumormicroenvironment (TME). Tumor-associated macrophages (TAMs) make up a large fraction of the TME and high levels of TAM have been associated with poor survival of cancer patients. In this study, the subcutaneous YUMM1.7 melanoma model was used to investigate the responsiveness to anti-PD-1 therapy. The tumor cell line was injected into GRf/f and GRf/f-LysMCre mice to enable insights into glucocorticoid-dependent effects within the myeloid compartment and how they contribute to the responsiveness to anti-PD-1 immunotherapy. Therefore, we profiled sorted CD45+ immune cells from tumors of GRf/f and GRf/f-LysMCre treated with anti-PD-1 therapy or an isotype control antibody via the cellular indexing of transcriptomes and epitomes-method (CITE-Seq).

ORGANISM(S): Mus musculus

PROVIDER: GSE292038 | GEO | 2026/03/15

REPOSITORIES: GEO

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CITE-Seq analysis of intratumoral immune cells from YUMM1.7 melanoma treated with anti-PD-1 therapy.

Project description:CITE-Seq analysis of intratumoral immune cells from YUMM1.7 melanoma treated with anti-PD-1 therapy.

| PRJNA1236367 | ENA

scRNA-seq analysis demonstrate alterations in TICs of the TME during TREM1 inhibition and anti-PD-1 treatment in B16F10 melanoma

Project description:To comprehensively characterize the changes within the TME during TREM1 deficiency and anti-PD-1 immune checkpoint blockade therapy, we performed scRNA-seq analysis of the CD45+ TICs in melanoma-bearing C57BL/6 mice receiving the various treatments. We analyzed approximately 8,249 CD45+ cells from the treatment groups with t-SNE analysis, identifying 10 distinct clusters of tumor-infiltrating immune cells

2023-09-27 | E-MTAB-13300 | biostudies-arrayexpress

Melanoma-intrinsic NR2F6 activity regulates anti-tumor immunity

Project description:Nuclear receptors (NRs) are implicated in the regulation of tumors and immune cells. We identify a tumor-intrinsic function of the orphan NR, NR2F6, regulating anti-tumor immunity. NR2F6 was selected from 48 candidate NRs, based on an expression pattern in melanoma patient specimens (i.e., IFN signature) associated with positive responses to immunotherapy and favorable patient outcomes. Correspondingly, genetic ablation of NR2F6 in a mouse melanoma model conferred a more effective response to PD-1 therapy. NR2F6 loss in B16F10 and YUMM1.7 melanoma cells attenuated tumor development in immune-competent but not -incompetent mice via the increased abundance of effector and progenitor-exhausted CD8+ T cells. Inhibition of NACC1 and FKBP10, identified as NR2F6 effectors, phenocopied NR2F6 loss. Remarkably, inoculation of NR2F6 KO mice with NR2F6 KD melanoma cells further decreased tumor growth compared with NR2F6 WT mice. Tumor-intrinsic NR2F6 function complements its tumor-extrinsic role and justifies the development of novel anti-cancer therapies.

2023-09-11 | GSE228162 | GEO

RNA localization to protrusions of mouse melanoma YUMM1.7 cells.

Project description:RNA localization to protrusions of mouse melanoma YUMM1.7 cells.

| PRJNA907013 | ENA

Expression changes in CD45neg subpopulation of YUMM1.7 melanoma pre MAPKi treatment vs. on MAPKi treatment [Y1.7.FPKM.batch3]

Project description:Treatment of advanced V600BRAF mutant melanoma using a BRAF inhibitor (BRAFi) or its combination with a MEKi typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPKi therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell-intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or -positive fractions,, implying tumor cell-intrinsic or stromal/immune alterations, respectively). Tumor cell-intrinsic reprogramming attenuated MAPK-dependency, while enhancing mesenchymal, angiogenic and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations.

2017-09-12 | GSE103712 | GEO

Expression changes in YUMM1.7 melanoma with/without PD-L2 overexpression under BRAFi treatment in NSG mice [Y1.7.FPKM.batch4]

2017-09-12 | GSE103713 | GEO

Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.

2022-03-31 | MSV000089180 | MassIVE

EZH2 loss during metabolic stress drives restoration of MHC Class I machinery in melanoma

Project description:Unleashing the immune anti-tumor response through immune checkpoint blockade (ICB) has been successful in treating many solid-tumor malignancies, including metastatic melanoma. When successful, the ICB response can be potent; however, half of patients fail to respond. ICB responsiveness is impacted by the harsh solid tumor microenvironment (TME), which is characterized by metabolic stress. The TME impacts tumor antigenicity, with ICB-responsive melanomas exhibiting increased major histocompatibility complex class I (MHC-I) expression. Further investigation of tumor immunogenicity in the context of the TME may improve cellular therapies. Here, we define and characterize an epigenetic mechanism regulating melanoma antigen presentation driven by prolonged metabolic stress. Murine and human melanoma cell lines were cultured under prolonged metabolic stress, forcing cells to adapt to the absence of glucose. Melanoma cells adapted to the absence of glucose have IFN-gamma-independent increases in MHC-I and an increased sensitivity to T cell-mediated killing. Proteomic analysis revealed dysregulation of histone epigenetic modifiers under prolonged metabolic stress, specifically loss of histone methyltransferase EZH2 (Enhancer of Zeste Homolog 2). EZH2 directly silences gene transcription via catalyzing H3K27me3. Following metabolic adaptation, ChIP-sequencing and ChIP-PCR revealed H3K27me3 loss at genes specific to MHC-I antigen presentation. Prolonged metabolic stress in melanoma cells blunt EZH2 levels and H3K27me3 levels at promoters of genes regulating MHC-I presentation, resulting in elevated MHC-I antigenicity and increased CD8+ T cell killing. This demonstrates potential for EZH2 abundance and mutational status as a prognostic indicators of ICB-responsiveness in metastatic melanoma and supports EZH2 inhibition as adjuvant for immunotherapies

2024-08-13 | MSV000095589 | MassIVE

Proteomic profiling of advanced melanoma to predict therapeutic response to anti-PD-1 therapy

Project description:Despite high clinical need, hardly any biomarker can accurately predict if patients with metastatic melanoma will respond to anti-PD-1 therapy. In this multicenter study we applied depletion and enrichment methods prior to different proteomic techniques to analyze the discovery cohort (n=56) and discovered several significantly regulated proteins as well as commonly enriched processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. We then analyzed two independent serum cohorts (n=96; n=17) confirming significant differences between R and NR. In addition, literature-based validation revealed 30 markers overlapping with previously published signatures, and survival analysis revealed that overexpression of 17 markers correlated with lower overall survival in melanoma patients. Primary melanoma tumor cells from NR also exhibit a distinctive immunophenotype characterized by CD29, CD49e, CD91, CD105, CD151, CD157, CD248 and CD280, and the TME could represent a potential target for therapy. Ultimately, this led to a potential marker signature with 8 key markers identified in at least two independent serum cohorts: CFHR3, CRP, LRG1, LYVE1, MMRN1, S100A8, SAA2, and TIMP1.

2023-08-18 | PXD039469 | Pride

Supplementation with α-ketoglutarate improved the efficacy of anti-PD1 melanoma treatment through epigenetic modulation of PD-L1

Project description:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.

2023-03-08 | GSE223110 | GEO

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