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Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Alan Berger

PROVIDER: E-GEOD-65041 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data in PD-L1 positive and PD-L1 negative human melanoma samples

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.

2015-05-01 | GSE65041 | 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

Tumor-derived small extracellular vesicle PD-L1 impedes macrophage-mediated antibacterial immunity in preexisting malignancy

Project description:Tumor-derived small extracellular vesicles (TEVs) were reported to carry various immunosuppressive molecules regulating immune response. We previously reported that TEV could express PD-L1 to systematically inhibit CD8 T cell anti-tumor immunity. Here, we observed that TEV PD-L1 suppressed the phagocytosis and bactericidal capacity of macrophages against E. coli. To investigate the potential mechanisms behind the impaired phagocytosis further, we collected and purified exosomes from the melanoma cell line B16-F10 PD-L1 knockout (KO) or vector culture to challenge RAW264.7 cells. We used RNA sequencing to reveal the key functional associated molecules for inhibiting the phagocytosis-associated pathway.

2024-10-24 | GSE275997 | GEO

RNA sequencing of PD-L1 knock down in uveal melanoma cells

Project description:In order to study the mechanism of nuclear PD-L1 in uveal melanoma, we knocked down PD-L1 and applied RNA-seq and CUT&Tag to identify its target genes in uveal melanoma.

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Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma.

Project description:LC-MS/MS targeted files submitted as support material for the paper: Quantitative mass spectrometry analysis of PD-L1 protein expression, N-glycosylation and expression stoichiometry with PD-1 and PD-L2 in human melanoma.

2016-12-21 | MSV000080433 | MassIVE

CD133+PD-L1+ cancer cells confer resistance to adoptively transferred engineered macrophage-based therapy in melanoma

Project description:Adoptive transfer of genetically or nanoparticle-engineered macrophages represents a promising cell therapy modality for treatment of solid tumor. However, the therapeutic efficacy is suboptimal without achieving a complete tumor regression, and the underlying mechanism remains elusive. Here, we discover a subpopulation of cancer cells with upregulated CD133 and programmed death-ligand 1 in mouse melanoma, resistant to the phagocytosis by the transferred macrophages. Compared to the CD133-PD-L1- cancer cells, the CD133+PD-L1+ cancer cells express higher transforming growth factor-β signaling molecules to foster a resistant tumor niche, that restricts the trafficking of the transferred macrophages by stiffened extracellular matrix, and inhibits their cell-killing capability by immunosuppressive factors. The CD133+PD-L1+ cancer cells exhibit tumorigenic potential. The CD133+PD-L1+ cells are further identified in the clinically metastatic melanoma. Hyperthermia reverses the resistance of CD133+PD-L1+ cancer cells through upregulating the ‘eat me’ signal calreticulin, significantly improving the efficacy of adoptive macrophage therapy. Our findings demonstrate the mechanism of resistance to adoptive macrophage therapy, and provide a de novo strategy to counteract the resistance.

2024-11-25 | GSE282386 | GEO

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis [RNA-seq, anti-PD-L1 therapy]

Project description:Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

2024-10-22 | GSE279750 | GEO

Global hypomethylation mediated changes regulate constitutive PD-L1 expression in melanoma [RRBS]

Project description:PD-L1 is a ligand for the inhibitory PD1 receptor on T cells and its expression in some cancers inhibits anti-cancer immune response. In melanoma, PD-L1 expression is induced in response to immune stimuli but in a proportion of melanomas it is constitutively expressed. Factors that drive constitutive expression of PD-L1 are unknown. Here we performed genome-scale methylation analysis of six cell lines that constitutively express PD-L1 (PD-L1 positive, referred to as PD-L1CON) and six cell lines that only express PD-L1 after treatment with IFN- (PD-L1 negative, referred to as PD-L1IND)

2018-05-24 | GSE107621 | GEO

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

Project description:MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby modulating activation of co-cultured T cells. During MAPKi therapy in vivo, tumor cell-intrinsic ITCH knockdown in murine melanoma induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-proficient mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented cytolytic CD8+ T-cell infiltration, and suppressed acquired resistance in BrafMUT, NrasMUT, and Nf1MUT murine melanoma and KrasMUT pancreatic cancer models. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the ability of ITCH over-expression to suppress MAPKi-resistance, supporting in vivo the ITCH–PD-L1–T-cell regulatory axis demonstrated in human cancer cell lines. Moreover, we identified a small-molecular ITCH activator which suppressed acquired MAPKi-resistance in vivo. Thus, MAPKi-elicited tumor-surface PD-L1 accelerates acquired-resistance, and degrading PD-L1 by activating ITCH may be a combinatorial approach to promote antitumor T-cell immunity and durable responses.

2022-05-31 | GSE199733 | GEO

Gene-expression profiles of PD-L1-affected CD8+ T cells

Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.

2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress

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