PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA665163 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12696800_1.fastq.gz | Fastqsanger.gz | |||
| SRR12696800_2.fastq.gz | Fastqsanger.gz | |||
| SRR12696801_1.fastq.gz | Fastqsanger.gz | |||
| SRR12696801_2.fastq.gz | Fastqsanger.gz | |||
| SRR12696802_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 190 |
Similar Datasets
Project description:Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti–PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n=26), or durvalumab and trametinib given concomitantly (cohort B, n=20) or sequentially (cohort C, n=22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti–PD-L1 therapy may provide treatment options for patients with advanced melanoma.
2020-09-24 | GSE158403 | GEO
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
Project description:Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.
| S-EPMC7721806 | biostudies-literature
Project description:Thirty-eight tumors from 17 patients treated with BRAF inhibitor (n=12) or combination BRAF/MEK inhibitors (n=5) with known PD-L1 expression were analyzed. RNA expression arrays were performed on all pre-treatment (PRE, n=17), early during treatment (EDT, n=8) and progression (PROG, n=13) biopsies. HLA-A/HLA-DPB1 expression was assessed by immunohistochemistry (IHC). Gene set enrichment analysis (GSEA) of PRE, EDT and PROG melanomas revealed that transcriptome signatures indicative of immune cell activation were strongly positively correlated with PD-L1 staining. In contrast, MAPK signaling and canonical Wnt/-ß-catenin activity were negatively associated with PD-L1 melanoma expression. The expression of PD-L1 and immune activation signatures did not simply reflect the degree or type of immune cell infiltration, and was not sufficient for tumor response to MAPK inhibition.
2017-07-01 | GSE99898 | GEO
Project description:Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance.
2021-08-19 | GSE177900 | GEO
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: Not available
| S-EPMC8360951 | biostudies-literature
Project description:Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance.
2021-08-19 | GSE177901 | GEO
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:Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS
| PRJNA507717 | ENA