Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA821314 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18531051_1.fastq.gz | Fastqsanger.gz | |||
| SRR18531051_2.fastq.gz | Fastqsanger.gz | |||
| SRR18531052_1.fastq.gz | Fastqsanger.gz | |||
| SRR18531052_2.fastq.gz | Fastqsanger.gz | |||
| SRR18531053_1.fastq.gz | Fastqsanger.gz |
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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
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:MAPK inhibitor (MAPKi) therapy in melanoma leads to the accumulation of tumor-surface PD-L1/L2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and downregulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation. During MAPKi therapy in vivo, melanoma cell-intrinsic ITCH knockdown induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-competent mice. Conversely, tumor cell-intrinsic ITCH overexpression reduced MAPKi-elicited PD-L1 accumulation, augmented intratumoral cytolytic CD8+ T cells, and suppressed acquired resistance in BrafV600MUT, NrasMUT, or Nf1MUT melanoma and KrasMUT-driven cancers. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 overexpression nullified the phenotype of ITCH overexpression, thereby supporting an in vivo ITCH-PD-L1-T-cell regulatory axis. Moreover, we identify a small-molecular ITCH activator that suppresses acquired MAPKi resistance in vivo. Thus, MAPKi-induced PD-L1 accelerates resistance, and a PD-L1-degrading ITCH activator prolongs antitumor response.SignificanceMAPKi induces tumor cell-surface PD-L1 accumulation, which promotes immune evasion and therapy resistance. ITCH degrades PD-L1, optimizing antitumor T-cell immunity. We propose degrading tumor cell-surface PD-L1 and/or activating tumor-intrinsic ITCH as strategies to overcome MAPKi resistance. This article is highlighted in the In This Issue feature, p. 1825.
| S-EPMC9357203 | 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:We found that the E3 ubiquitin ligase Itch significantly affects early B-cell differentiation. To explore the role of Itch in late B-cell differentiation, we sorted B cells from WT and Itch KO mice. To explore the effect of Itch deficency on gene expression, we determined mRNA profiles in B cells from WT and Itch KO mice by RNA-seq. RNA-seq was done with an Illumina HiSeq 2500 instrument at GENEWIZ, Suzhou, China.
2020-03-01 | E-MTAB-8273 | biostudies-arrayexpress
Project description:We found that the E3 ubiquitin ligase Itch significantly affects early B-cell differentiation. To explore the role of Itch in late B-cell differentiation, we sorted B cells from WT and Itch cKO mice. To explore the effect of Itch deficency on gene expression, we determined mRNA profiles in B cells from WT and Itch cKO mice by RNA-seq. RNA-seq was done with an Illumina HiSeq 2500 instrument at GENEWIZ, Suzhou, China.
2020-03-01 | E-MTAB-8281 | biostudies-arrayexpress
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:To test the hypothesis that defects in the termination of inflammatory signaling led to skin inflammation that results in the “Itchy” phenotype, we isolated RNA from the lesional skin of Itch-/- mice and from the skin of wild-type mice and performed genome-wide mRNA expression profiling by RNA sequencing. We ranked genes based on the fold change in their expression (increased or decreased) in Itch-/- skin relative to that in wild-type skin. The expression of several TNF–induced genes were increased in Itch-/- skin, including, IL-1?, IL-6, IL-11, IL-19, IL-1RL1, CCL4, CXCL3, CXCL2, CCL3, and CD14. mRNA profiles comparison between wild type (WT) skin and Itch-/- mice lesional skin
2015-03-04 | E-GEOD-65686 | biostudies-arrayexpress
Project description:In the present study, RNA-seq were performed To identify clinical relevance of PLAUR, a putative Serpin E1 receptor, in cutaneous itch signaling and crosstalk pathways with other critical itch modulators.mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. Our experiment showed Serpin E1-treatment further led to a marked upregulation of TLR2 transcript in mDRG neurons, along with enhanced transcription of cosignaling proteins belonging to pro-inflammatory signaling pathways including NF-κB signaling proteins. We next investigated the consequence of TLR2 activation in mTGNs using the TLR agonists, Pam3CSK4 (TLR1/2 agonist), FSL-1 (TLR2/6 agonist), or vehicle. Among these transcripts, TLR2 was found upregulated strongest by both TLR2 agonists suggesting a selfenhancing feedback loop of TLR2 activation.The PLAUR-TLR2 axis promotes cutaneous inflammation and itch, both feeding into an aggravation of AD. This finding might help us to better understand the skin-nerve communication in itch circuits.
2022-08-03 | GSE189333 | GEO
Project description:The E3 ubiquitin ligase Itch regulates antibody levels and prevents autoimmune disease in humans and mice, yet how Itch regulates B cell fate or function is unknown. We now show that Itch directly limits B cell activity. Using LC-MSMS, we profiled and compared the whole cell proteomes of Itch deficient and Itch sufficient CpG-stimulated B cells. B cells lacking Itch exhibited increased levels of mTORC1 targets and E2F transcription factor targets. These results support a novel role for Itch in limiting B cell metabolism and proliferation.
2019-07-12 | PXD014243 | Pride