Dataset Information

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

ABSTRACT:

Background

Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.

Methods

Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.

Results

58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10^-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.

Conclusions

Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

SUBMITTER: Ye W

PROVIDER: S-EPMC8110747 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

Ye Weiyu W Olsson-Brown Anna A Watson Robert A RA Cheung Vincent T F VTF Morgan Robert D RD Nassiri Isar I Cooper Rosalin R Taylor Chelsea A CA Akbani Umair U Brain Oliver O Matin Rubeta N RN Coupe Nicholas N Middleton Mark R MR Coles Mark M Sacco Joseph J JJ Payne Miranda J MJ Fairfax Benjamin P BP

British journal of cancer 20210315 10

<h4>Background</h4>Immune checkpoint blockers (ICBs) activate CD8<sup>+</sup> T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.<h4>Methods</h4>Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination ...[more]

PMID: 33723392

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Project description:IntroductionA high proportion of metastatic melanoma patients do not respond to immune checkpoint inhibitors (ICI), and until now, no validated biomarkers for response and survival have been known.MethodsWe performed a retrospective analysis of outcomes in patients with metastatic melanoma treated with first-line ICI at the Institute of Oncology Ljubljana from January 2018 to December 2020. The immune-related adverse events (irAEs) and serum immune-inflammation parameters (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (LR), systemic immune-inflammation index (SII) and pan-immune-inflammation value (PIV)) were analyzed as potential biomarkers for response and survival. Survival rates were calculated using the Kaplan-Meier method and then compared with the log-rank test. Multivariate regression Cox analysis was used to determine independent prognostic factors for progression-free survival (PFS) and overall survival (OS).ResultsMedian follow-up was 22.5 months. The estimated median progression-free survival (PFS) was 15 months (95% CI 3.3-26.2). The two-year survival rate (OS) was 66.6%. Among 129 treated patients, 24 (18.6%) achieved complete response, 28 (21.7%) achieved partial response, 26 (20.2%) had stable disease and 51 (39.5%) patients experienced a progressive disease. There was a higher response rate in patients with irAEs (p < 0.001) and high NLR before the second cycle of ICI (p = 0.052). Independent prognostic factors for PFS were irAE (HR 0.41 (95% CI 0.23-0.71)), SII before the first cycle of ICI (HR 1.94 (95% CI 1.09-3.45)) and PLR before the second cycle of ICI (HR 1.71 (95% CI 1.03-2.83)). The only independent prognostic factor for OS was SII before the first cycle of ICI (HR 2.60 (95% CI 0.91-7.50)).ConclusionsPatients with high pre-treatment levels of SII had a higher risk of progression and death; however, patients with irAEs in the high-SII group might respond well to ICI. Patients who develop irAEs and have high NLRs before the second ICI application have higher rates of CR and PR, which implicates their use as early biomarkers for responsiveness to ICI.

Project description:PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n=16), mucosal (n=36), uveal (n=103), and chronic sun-damaged (CSD) (n=45) melanomas (24 lentigo maligna, 13 'mixed' desmoplastic, and 8 'pure' desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P=0.0002) and higher in CSD (P=0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate-severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P=0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

Project description:BackgroundCheckpoint inhibitors, such as PD-1 inhibitors (nivolumab, pembrolizumab) and anti-CTLA-4 (CD152) (ipilimumab), are widely used in metastatic melanoma, and most immune-related adverse events are known. Several cardiovascular AEs (CVAEs) associated with immune checkpoint inhibitor exposure have been reported in post-marketing surveillance studies and represent major issues for patients with melanoma during and after cancer treatment. Data on CVAES induced by immune checkpoint inhibitors in melanoma, especially incidence and risk factors, are lacking.MethodsA systematic review of the literature up to 31 August 2020 was performed in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and the ClinicalTrials.gov register according to prespecified selection criteria from inception to 7 April 2020. Statistics were performed on 3289 patients from five randomized clinical trials on melanoma.ResultsPatients with melanoma treated with immune checkpoint inhibitors had a significant risk of presenting dyslipidemia (Peto OR: 4.74, 95% CI: 2.16-10.41, p < 0.01, I2 = 0%, p = 0.94). The Peto OR was numerically significant for pericarditis, myocarditis, heart failure, myocardial infarction, cerebral ischemia, high pulmonary pressure, blood high pressure, arrhythmias, endocarditis, and conduction disturbances, but the confidence interval was not significant. The risk of CVAEs was not statistically different between melanoma treated with immune checkpoint inhibitors and other tumors treated with immune checkpoint inhibitors (range of p-value from 0.13 to 0.95). No interaction between follow-up length and CVAE reporting was found.ConclusionsOur study underlines that checkpoint inhibitors used for melanoma increase CVAEs, especially dyslipidemia, which could pave the way to chronic inflammatory processes, atherosclerosis, and, finally, ischemic cardiopathy. These cardiovascular adverse events could be acute or delayed, justifying the monitoring of lipidic biology and a baseline cardiology consultation.

Dataset Information

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

Background

Methods

Results

Conclusions

Publications

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

Similar Datasets

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