Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients

Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD-1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and response to therapy. In this prospective observational study, plasma cytokine levels and PD-1, PD-L1 and PD-L2 expression was evaluated in circulating CD3(+), CD3(+)CD4(+) and CD3(+)CD8(+) cells from 70 treatment-naïve patients with advanced NSCLC (Stage IIIB and IV) and from 10 healthy donors. The primary objective was to assess OS according to PD-1, PD-L1, PD-L2 expression status on PBMCs and lymphocyte subsets. Our results indicate that the percentage of PD-L1(+)CD3(+), PD-L1(+)CD3(+)CD8(+) PD-L2(+)PBMCs, PD-L2(+)CD3(+), PD-L2(+)CD3(+)CD4(+) cells was higher in patients than in healthy donors. Survival was decreased among patients with a high percentage of either PD-1(+)PBMCs, PD-1(+)CD3(+), PD-L1(+)CD3(+), PD-L1(+)CD3(+)CD8(+), PD-L2(+)CD3(+), PD-L2(+)CD3(+)CD4(+), or PD-L2(+)CD3(+)CD8(+) cells. IL-2 and TNF-α showed the strongest association with PD-L1 and PD-L2 expression on specific subsets of T-lymphocytes. Our findings suggest that increased PD-1/PD-L1/PDL-2 expression in PBMCs, particularly in T-cells, may be an additional mechanism leading to tumor escape from immune control. This study is registered with ClinicalTrials.gov, number NCT02758314.