Dataset Information

Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy.

ABSTRACT: A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally validated by bootstrapping. For SNPs with a statistical significance, an expression quantitative trait loci (eQTL) analysis was performed. In a subset of patients, immunophenotyping was performed. Patients with a SNP in PDCD1 (804C > T; rs2227981) had a significantly poorer OS with a 3-year OS rate of 51.8%, as compared to 71% in wild type patients (hazard ratio [HR] 2.37; 95% CI: 1.11-5.04; p = 0.026). eQTL analysis showed that this SNP was associated with decreased gene expression. In addition, PDCD1 804C > T carriers had a reduced fraction of peripheral PD-1+CD4+ T cells. No other associations between SNPs and OS were found. PDCD1 804C > T is associated with poorer OS after anti-PD-1 monotherapy in patients with metastatic melanoma. This SNP may affect clinical benefit from ICIs by decreasing transcription initiation and expression of PD-1 in T cells.

SUBMITTER: de With M

PROVIDER: S-EPMC8002987 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Germline Variation in <i>PDCD1</i> Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy.

de With Mirjam M Hurkmans Daan P DP Oomen-de Hoop Esther E Lalouti Ayoub A Bins Sander S El Bouazzaoui Samira S van Brakel Mandy M Debets Reno R Aerts Joachim G J V JGJV van Schaik Ron H N RHN Mathijssen Ron H J RHJ van der Veldt Astrid A M AAM

Cancers 20210318 6

A substantial number of melanoma patients do not benefit from therapy with anti-PD-1. Therefore, we investigated the predictive value of single nucleotide polymorphisms (SNPs) in genes related to the PD-1 axis in patients with metastatic melanoma. From 119 consecutive melanoma patients who were treated with pembrolizumab or nivolumab monotherapy, blood samples were genotyped for 11 SNPs in nine genes. Associations between SNPs and OS were tested using Cox regression analysis and internally valid ...[more]

PMID: 33803602

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Project description:The blockade of programmed cell death protein 1 (PD-1) as monotherapy has been widely used in melanoma, but to identify melanoma patients with survival benefit from anti-PD-1 monotherapy is still a big challenge. There is an urgent need for prognostic signatures improving the prediction of immunotherapy responses of these patients. We analyzed transcriptomic data of pre-treatment tumor biopsies and clinical profiles in advanced melanoma patients receiving only anti-PD-1 monotherapy (nivolumab or pembrolizumab) from the PRJNA356761 and PRJEB23709 data sets as the training and validation cohort, respectively. Weighted gene co-expression network analysis was used to identify the key module, then least absolute shrinkage and selection operator was conducted to determine prognostic-related long noncoding RNAs (lncRNAs). Subsequently, the differentially expressed genes between different clusters were identified, and their function and pathway annotation were performed. In this investigation, 92 melanoma patients with complete survival information (51 from training cohort and 41 from validation cohort) were included in our analyses. We initiallyidentified the key module (skyblue) by weighted gene co-expression network analysis, and then identified a 15 predictive lncRNAs (AC010904.2, LINC01126, AC012360.1, AC024933.1, AL442128.2, AC022211.4, AC022211.2, AC127496.5, NARF-AS1, AP000919.3, AP005329.2, AC023983.1, AC023983.2, AC139100.1, and AC012615.4) signature in melanoma patients treated with anti-PD-1 monotherapy by least absolute shrinkage and selection operator in the training cohort. These results were then validated in the validation cohort. Finally, enrichment analysis showed that the functions of differentially expressed genes between two consensus clusters were mainly related to the immune process and treatment. In summary, the 15 lncRNAs signature is a novel effective predictor for prognosis in advanced melanoma patients treated with anti-PD-1 monotherapy.

Project description:BackgroundDespite improvements in the treatment of primary uveal melanoma (UM), patients with metastatic disease continue to exhibit poor survival.MethodsA retrospective review of metastatic UM patients at Yale (initial cohort) and Memorial Sloan Kettering (validation cohort) was conducted. Cox proportional hazards regression was used to determine baseline factors that are associated with overall survival, including sex, Eastern Cooperative Oncology Group (ECOG) Performance Status Scale, laboratory measurements, metastasis location, and use of anti-CTLA-4 and anti-PD-1 therapies. Differences in overall survival were analyzed using Kaplan-Meier analysis.ResultsA total of 89 patients with metastatic UM were identified; 71 and 18, in the initial and validation cohorts, respectively. In the initial cohort, median follow-up was 19.8 months (range, 2-127 months) and median overall survival was 21.8 months (95% CI, 16.6-31.3). Female sex, anti-CTLA-4, and anti-PD-1 therapy were associated with better survival outcomes with adjusted death hazard ratios (HRs) of 0.40 (95% CI, 0.20-0.78), 0.44 (0.20-0.97), and 0.42 (0.22-0.84), respectively, whereas development of hepatic metastases and ECOG score ≥1 (per 1 U/L) were associated with worse survival outcomes with HRs of 2.86 (1.28-7.13) and 2.84 (1.29-6.09), respectively. In both the initial and validation cohorts, use of immune checkpoint inhibitors was associated with improved overall survival after adjusting for sex and ECOG score, with death HRs of 0.22 (0.08-0.56) and 0.04 (0.002-0.26), respectively.ConclusionsDevelopment of extrahepatic-only metastases, ECOG of 0, immune checkpoint therapy, and female sex were each associated with more than 2-fold reductions in risk of death.Plain language summaryMetastatic uveal melanoma patients face limited treatment options and poor survival rates. Results from this retrospective analysis indicate that immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 therapies, were associated with improved survival outcomes. Factors such as extrahepatic-only metastases, better baseline performance status, and female sex contributed to a more than 2-fold reduction in death risk. These findings highlight the potential of immunotherapy in treating metastatic uveal melanoma.

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Project description:BackgroundUveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis.MethodsWe collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival.ResultsCompared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy.ConclusionThe results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.

Dataset Information

Germline Variation in PDCD1 Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy.

Publications

Germline Variation in <i>PDCD1</i> Is Associated with Overall Survival in Patients with Metastatic Melanoma Treated with Anti-PD-1 Monotherapy.

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