title: Analysis of the prognostic role of an immune checkpoint score in resected non-small cell lung cancer patients.
abstract: Tumors develop mechanisms to recruit tolerogenic immune cells and to induce the expression of molecules that act as immune checkpoints. This regulation of the immune microenvironment favors immune tolerance to the neoplastic cells. In this study, we have investigated the prognostic role of immune-checkpoint expression markers in a cohort of resectable non-small cell lung cancer (NSCLC) patients. RNA was isolated from fresh-frozen lung specimens (tumor and normal lung) (n= 178). RTqPCR was performed to analyze the relative expression of 20 immune-related genes that were normalized by the use of endogenous genes selected by GeNorm algorithm. Patients with higher expression levels ofIL23AandLGALS2presented better outcomes. In the clustering expression patterns, we observed that patients with higher expression of immunoregulatory genes had better survival rates. Additionally, these data were used to develop a gene expression score. SinceCTLA4andPD1were associated with prognosis based on Cox regression analysis (Z-score > 1.5), a multivariate model including these two genes was created. Absolute regression coefficients from this analysis were used in order to calculate the immune-checkpoint score: (PD1×0.116) + (CTLA4×0.059) for each case. Kaplan-Meier survival analysis showed that patients with high immune-checkpoint score have longer overall survival (OS) [NR vs. 40.4 mo,p= 0.008] and longer relapse-free survival (RFS) [82.6 vs. 23 mo,p= 0.009]. Multivariate analysis in the entire cohort indicated that the immune-checkpoint score was an independent biomarker of prognosis for OS [HR: 0.308; 95% CI, 0.156-0.609;p= 0.001] and RFS [HR: 0.527; 95% CI, 0.298-0.933;p= 0.028] in early-stage NSCLC patients. In conclusion, this score provides relevant prognostic information for a better characterization of early stage NSCLS patients with strikingly different outcomes and who may be candidates for immune-based therapies.
authors.affiliation: Department of Medicine, Universitat de València, Valencia, Spain; Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Usó
authors.affiliation: Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain; Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Eloísa
authors.identifier: 0000-0001-7395-4380
authors.initials: E
authors.lastname: Jantus-Lewintre
authors.affiliation: Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain; Department of Pathology, Universitat de Valencia, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig-Fariñas
authors.affiliation: Medical Oncology Department, Hospital General Universitario de Valencia , Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Blasco
authors.affiliation: Department of Thoracic Surgery, Hospital General Universitario de Valencia , Valencia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: García Del Olmo
authors.affiliation: Department of Thoracic Surgery, Hospital General Universitario de Valencia , Valencia, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Guijarro
authors.affiliation: Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Department of Pathology, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martorell
authors.affiliation: Department of Medicine, Universitat de València, Valencia, Spain; Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Camps
authors.affiliation: Molecular Oncology Laboratory, Fundación Investigación, Hospital General Universitario de Valencia, Valencia, Spain; Department of Biotechnology, Universitat Politècnica de València, Valencia, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain.
authors.forename: Rafael
authors.identifier: 0000-0001-9162-8490
authors.initials: R
authors.lastname: Sirera
keywords: Biomarker; NSCLC; checkpoint score; prognostic