Blood Immune Cell Biomarkers in Patient With Lung Cancer Undergoing Treatment With Checkpoint Blockade

Abstract

Characterization of host immune cell parameters before and during immunotherapy is expected to identify predictive biomarkers for clinical outcome. We prospectively monitored blood immune cells from 35 patients with advanced non-small cell lung cancer undergoing checkpoint inhibitor monotherapy. The aim was to identify parameters correlating with better/worse outcome. Peripheral blood was serially collected before each infusion at the onset and at cycle 3 and 5 of immunotherapy. A complete leukocyte blood count, the lymphocytic subpopulations and the percentages of both HLA-DR monocytes and dendritic cells (DC) were monitored. Disease control was defined as partial/complete response and stable disease on computed tomography scan according to RECIST 1.1. The predictive value of the immune cell parameters investigated was evaluated by patients' survival analysis. Forty percent of patients showed a clinical response, and the global median overall survival was 7.0 months (95% confidence interval: 3.5-10.5). Patients with an initial neutrophil-to-lymphocyte ratio (NLR) ≥5.2, and/or an amount of HLA-DR monocytes ≥11% and/or a total DC level ≤0.4% of leukocytes did rarely respond to PD-1 inhibitor therapy. Otherwise, the immunotherapy-induced decrease of the neutrophil-to-lymphocyte ratio and/or HLA-DR monocytes and the increase of total DC frequencies were correlated with improved therapy response and prolonged overall survival. Blood values in the third cycle of immunotherapy did already reflect the effects observed. On the basis of the 3 immune cell parameters identified we created 3 different variants of scores that enable to stratify patients into groups of risk/therapy response. Our results warrant further investigation in larger prospective clinical trials for validation.

FIGURE 1

PFS for patients grouped below and above cutpoint for the parameters NLR (HR, 3.0; P=0.009), HLA-DR^low monocytes (HR, 3.85; P=0.011) and total DC levels (HR, 4.35; P=0.003), estimated at the onset of checkpoint therapy. In Kaplan-Meier plots, patients with censored values are denoted by tick marks. Patient number (n) is given for each group and the mean±standard error of the estimated PFS. DC indicates dendritic cell; HR, hazard ratio; NLR, neutrophil-lymphocyte ratio; MDSC, myeloid-derived suppressor cell; PFS, progression-free survival.

FIGURE 2

Time course of blood immune cell markers in the patients’ groups progression (P), stable disease (S) and partial/complete response (R) with values at the onset of checkpoint therapy set to 100%. Mean values and error bars (95%) are displayed. DC indicates dendritic cell; NLR, neutrophil-lymphocyte ratio; MDSC, myeloid-derived suppressor cell.

FIGURE 3

PFS and OS for patients grouped below and above cutpoint of 3 score variants (A, B, C), with the patient number and mean survival time±standard error. Tick marks indicate censored observations. OS indicates overall survival; PFS, progression-free survival.