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

// Oscar Arrieta 1, * , Edgar Montes-Servín 1, * , Juan-Manuel Hernandez-Martinez 1, 2, * , Andrés F. Cardona 3 , Eibar Casas-Ruiz 1 , José C. Crispín 4 , Daniel Motola 5 , Diana Flores-Estrada 1 and Lourdes Barrera 1 1 Functional Unit of Thoracic Oncology and Laboratory of Personalized Medicine, Instituto Nacional de Cancerología, Mexico City, Mexico 2 CONACyT-Instituto Nacional de Cancerología, Mexico City, Mexico 3 Clinical and Translational Oncology Group, Institute of Oncology, Clínica del Country, Bogotá, Colombia 4 Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico 5 Centro Oncológico, Hospital Médica Sur, Mexico City, Mexico * These authors have contributed equally to this work Correspondence to: Oscar Arrieta, email: ogar@unam.mx Keywords: immunotherapy; checkpoint inhibitors; lung adenocarcinoma; prognosis; circulating lymphocytes Received: August 06, 2017 Accepted: September 03, 2017 Published: October 24, 2017 ABSTRACT 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.