Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant.,Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients.,Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified.,NLR was calculated before treatment and at 3-week intervals after treatment initiation until 9 weeks.,Baseline NLR was tested for association with overall survival (OS), progression free survival (PFS), and clinical response to treatment.,On-treatment NLRs were tested for association with the same outcomes using landmark survival analyses and time-dependent Cox regression models.,The association of relative change of NLR from baseline with outcomes was also examined.,A multivariate model tested the association of NLR and OS/PFS with additional clinical factors.,There were 197 IPI patients and 65 BRAFi patients.,In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03-3.37, p < 0.001), PFS (HR 1.81-2.51, p < 0.001), and response to therapy (OR 3.92-9.18, p < 0.007), in the IPI cohort.,In addition, a > 30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p < 0.004).,In BRAFi patients, NLR was not consistently associated with outcomes.,A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma.,An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients.,In comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may have a uniquely predictive value in patients treated with immunotherapy.,•Neutrophil to lymphocyte ratio is associated with important clinical outcomes in melanoma patients treated with ipilimumab.,•Changes in neutrophil to lymphocyte ratio from baseline during treatment with ipilimumab correlate with clinical outcomes•Neutrophil to lymphocyte ratio is not associated with outcomes in those treated with BRAF inhibitors,Neutrophil to lymphocyte ratio is associated with important clinical outcomes in melanoma patients treated with ipilimumab.,Changes in neutrophil to lymphocyte ratio from baseline during treatment with ipilimumab correlate with clinical outcomes,Neutrophil to lymphocyte ratio is not associated with outcomes in those treated with BRAF inhibitors,Baseline neutrophil to lymphocyte ratio (NLR) and changes in NLR during treatment associate with important clinical outcomes, including overall survival, progression-free survival, and clinical response in advanced melanoma patients treated with immunotherapy, and therefore may have a valuable role in selecting patients most likely or least likely to benefit from treatment, or for monitoring response to treatment over time.,This marker is not useful in patients treated with BRAF inhibitors, perhaps reflecting its unique value in immunotherapy.
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1-5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy.,We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR).,In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size.,Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire.,Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients.,Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.