Dataset Information

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response

ABSTRACT: Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Melanoma

SUBMITTER: John Koomen

LAB HEAD: Joseph Markowitz, MD/PhD

PROVIDER: PXD033340 | Pride | 2022-04-21

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20171012_Markowitz-FFPE-18001.raw	Raw
	20171012_Markowitz-FFPE-18001.raw__F008365_.dta	Raw
	20171012_Markowitz-FFPE-18001.raw__F008365_.mzid.gz	Mzid
	20171012_Markowitz-FFPE-18001.raw__F008365_.mzid_20171012_Markowitz-FFPE-18001.raw__F008365_.MGF	Mzid
	20171012_Markowitz-FFPE-18002.raw	Raw

Items per page:

1 - 5 of 216

Publications

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response.

Garg Saurabh K SK Welsh Eric A EA Fang Bin B Hernandez Yuliana I YI Rose Trevor T Gray Jhanelle J Koomen John M JM Berglund Anders A Mulé James J JJ Markowitz Joseph J

Cancers 20201126 12

Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The pa ...[more]

PMID: 33255891

Similar Datasets

Project description:Gene expression data of HER2+ breast tumor samples Increasing evidence indicates that a subset of patients with HER2-positive breast cancer may achieve significant clinical benefit with anti-HER2 targeted therapy without chemotherapy. Thus, identification of biomarkers of long-term benefit from anti-HER2 agents is needed, especially in the metastatic setting. In the HERLAP study (NCT00842998), patients with HER2-positive metastatic breast cancer were randomized to trastuzumab or lapatinib as first-line therapy. Patients showing radiological signs of tumor regression after 8 weeks of treatment were allowed to continue on single agent anti-HER2 therapy until disease progression. Chemotherapy was added to anti-HER-2 therapy in patients failing to achieve tumor regression at the 8-week evaluation and those progressing at any time. Expression analysis of 105 selected genes was performed from formalin-fixed paraffin-embedded in 17 primary tumor samples. The research-based PAM50 intrinsic subtypes were also identified. The association of the expression of each biomarker with clinical outcome endpoints was evaluated. Nineteen patients were enrolled. In 4 patients (21.1%) we observed disease control lasting longer than 12 months with single agent anti-HER2 therapy (range 14.9-38.8 months). High expression of 17q12-21 amplicon genes HER2 and GRB7, and the PAM50 HER2-enriched intrinsic profile, were found significantly associated with 8-week overall response rate and with the duration of disease control during single agent anti-HER2 therapy. Conversely, high expression of luminal-related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile, was found associated with reduced benefit from single agent anti-HER2 therapy. Conclusions: Our data indicate that gene expression-based biomarkers can identify patients with HER2-positive metastatic breast cancer that benefit substantially from single agent chemo-free anti-HER2 targeted therapy. In the study presented here, a well-defined cohort of 21 breast cancer cases from the HERLAP trial, was used to acquire expression profiles of a total of 105 unique genes

Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.