Dataset Information

Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

ABSTRACT: Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and there is an urgent need to understand and mitigate mechanisms of resistance. MicroRNAs are key post-transcriptional regulators of gene expression that regulate many aspects of cancer biology, including immune evasion. We used network analysis to define two core microRNA-mRNA networks in melanoma tissues and cell lines corresponding to 'MITF-low' and 'Keratin' transcriptomic subsets of melanoma. We then evaluated expression of these core microRNAs in pre-PD-1-inhibitor-treated melanoma patients and observed that higher expression of miR-100-5p and miR-125b-5p were associated with significantly improved overall survival. These findings suggest that miR-100-5p and 125b-5p are potential markers of response to PD-1 inhibitors, and further evaluation of these microRNA-mRNA interactions may yield further insight into melanoma resistance to PD-1 inhibitors.

SUBMITTER: Sloane RAS

PROVIDER: S-EPMC8582574 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

Sloane Robert A Szczepaniak RAS White Michael G MG Witt Russell G RG Banerjee Anik A Davies Michael A MA Han Guangchun G Burton Elizabeth E Ajami Nadim N Simon Julie M JM Bernatchez Chantale C Haydu Lauren E LE Tawbi Hussein A HA Gershenwald Jeffrey E JE Keung Emily E Ross Merrick M McQuade Jennifer J Amaria Rodabe N RN Wani Khalida K Lazar Alexander J AJ Woodman Scott E SE Wang Linghua L Andrews Miles C MC Wargo Jennifer A JA

Cancers 20211022 21

Metastatic melanoma is a deadly malignancy with poor outcomes historically. Immuno-oncology (IO) agents, targeting immune checkpoint molecules such as cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and programmed cell death-1 (PD-1), have revolutionized melanoma treatment and outcomes, achieving significant response rates and remarkable long-term survival. Despite these vast improvements, roughly half of melanoma patients do not achieve long-term clinical benefit from IO therapies and ther ...[more]

PMID: 34771465

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Project description:PurposeBlocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.MethodsPubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.FindingsThe anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.ImplicationsThis family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Project description:ImportanceImmune checkpoint blockade (ICB) has improved the survival of patients with advanced melanoma. Durable responses are observed for 40% to 60% of patients, depending on treatment regimens. However, there is still large variability in the response to treatment with ICB, and patients experience a range of immune-related adverse events of differing severity. Nutrition, through its association with the immune system and gut microbiome, is a poorly explored but appealing target with potential to improve the efficacy and tolerability of ICB.ObjectiveTo investigate the association between habitual diet and response to treatment with ICB.Design, setting, and participantsThis multicenter cohort study (the PRIMM study) was conducted in cancer centers in the Netherlands and UK and included 91 ICB-naive patients with advanced melanoma who were receiving ICB between 2018 and 2021.ExposuresPatients were treated with anti-programmed cell death 1 and anti-cytotoxic T lymphocyte-associated antigen 4 monotherapy or combination therapy. Dietary intake was assessed through food frequency questionnaires before treatment.Main outcomes and measuresClinical end points were defined as overall response rate (ORR), progression-free survival at 12 months (PFS-12), and immune-related adverse events that were grade 2 or higher.ResultsThere were a total of 44 Dutch participants (mean [SD] age, 59.43 [12.74] years; 22 women [50%]) and 47 British participants (mean [SD] age, 66.21 [16.63] years; 15 women [32%]). Dietary and clinical data were prospectively collected from 91 patients receiving ICB between 2018 and 2021 for advanced melanoma in the UK and the Netherlands. Logistic generalized additive models revealed positive linear associations between a Mediterranean dietary pattern that was high in whole grains, fish, nuts, fruit, and vegetables and the probability of ORR and PFS-12 (probability of 0.77 for ORR; P = .02; false discovery rate, 0.032; effective degrees of freedom, 0.83; probability of 0.74 for PFS-12; P = .01; false discovery rate, 0.021; effective degrees of freedom, 1.54).Conclusions and relevanceThis cohort study found a positive association between a Mediterranean diet, a widely recommended model of healthy eating, and response to treatment with ICB. Large prospective studies from different geographies are needed to confirm the findings and further elucidate the role of diet in the context of ICB.

Project description:PurposeDrug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.Experimental designA total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed.ResultsThe overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87-21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67-86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration.ConclusionsPriming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma.SignificanceThere are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.

Dataset Information

Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

Publications

Identification of MicroRNA-mRNA Networks in Melanoma and Their Association with PD-1 Checkpoint Blockade Outcomes.

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