Combined Immunoscore for Prognostic Stratification of Early Stage Non-Small-Cell Lung Cancer.

Alice Boscolo,Jessica Menis,Federico Rea,Giovanni Comacchio,Loredana Urso,Francesco Fortarezza,Laura Bonanno,Pierfranco Conte,Stefano Frega,Fiorella Calabrese,Giulia Pasello,Valentina Guarneri,Francesca Lunardi

doi:10.3389/fonc.2020.564915

Abstract

BackgroundTo date, no combined immunoscore has been evaluated for prognostic stratification of early stage non-small-cell lung cancer (NSCLC). The main goal of this study was to investigate the prognostic impact of programmed death ligand 1 (PD-L1) expression and different immune cell components (CD4+, CD8+ T-lymphocytes, and CD68+ macrophages) in early stage NSCLC patients, distinguishing peritumoral (PT) and intratumoral (IT) localizations. The secondary aim was to identify a combined immunoscore to optimize the prognostic stratification of NSCLC patients.MethodsThis retrospective study included surgical specimens from consecutive chemo-naive stage II–III radically resected NSCLC patients. Immunohistochemistry was carried out to evaluate PD-L1 expression and to quantify IT and PT CD4+, CD8+ T-lymphocytes, and CD68+ macrophages. The impact of a single marker and of a combination of multiple markers on overall survival (OS) was investigated.ResultsSeventy-nine patients were included in the study. PD-L1 expression was associated with worse prognosis (3 years OS: 58% in high- compared with 67% in low-expressing tumors), even though without statistical significance. When integrating PT CD8+, CD4+, and CD68 into a combined PT immunoscore, a significant prognostic stratification of patients was obtained and confirmed at multivariate analysis (3 years OS: 86% in patients with low PT immunoscore vs. 59% in patients with high PT immunoscore, p = 0.018). The integration of derived neutrophil/lymphocyte ratio (dNLR) with combined PT immunoscore improved prognostic stratification, with longer OS in patients with low PT immunoscore and low dNLR (p = 0.002).ConclusionThe combined PT immunoscore (CD8+, CD4+, and CD68) integrated with dNLR may be a promising marker for the development of an integrated Tumor, Node, Metastasis (TNM) immunoscore.

Highlights

Lung cancer is still the leading cause of cancer-related death worldwide, and non-small-cell lung cancer (NSCLC) accounts for about 85% of cases compared with 15% of small-cell lung cancer (SCLC) [1].Only about 20–25% of NSCLC may be considered as radically resectable and potentially curable, with variable prognosis depending on the Tumor, Node, Metastasis (TNM) stage [1].Five-year survival rate in surgical cases is improved by 4% with adjuvant chemotherapy, which currently has a role in good performance status patients with stage II and III NSCLC [2].Histologic subtype and stage according to the TNM classification system are currently the main reference tools driving the decision-making process in these patients
Some works on early stage radically resected NSCLC have previously associated tumor-infiltrating lymphocytes (TILs) and immune checkpoint expression, such as programmed death ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3), with patient’s prognosis [5,6,7,8,9,10]
A recent meta-analysis focusing on the prognostic value of tumor microenvironment (TME) immune cells of early stage lung cancer revealed that, after adjusting for important clinical covariates, higher levels of CD8+ cytotoxic T cells, CD20+ B cells, and CD 56/57+ natural killer (NK) cells seem to be associated with a better prognosis

Summary

Introduction

Lung cancer is still the leading cause of cancer-related death worldwide, and non-small-cell lung cancer (NSCLC) accounts for about 85% of cases compared with 15% of small-cell lung cancer (SCLC) [1].Only about 20–25% of NSCLC may be considered as radically resectable and potentially curable, with variable prognosis depending on the Tumor, Node, Metastasis (TNM) stage [1].Five-year survival rate in surgical cases is improved by 4% with adjuvant chemotherapy, which currently has a role in good performance status patients with stage II and III NSCLC [2].Histologic subtype and stage according to the TNM classification system are currently the main reference tools driving the decision-making process in these patients. About 20–25% of NSCLC may be considered as radically resectable and potentially curable, with variable prognosis depending on the Tumor, Node, Metastasis (TNM) stage [1]. Some works on early stage radically resected NSCLC have previously associated tumor-infiltrating lymphocytes (TILs) and immune checkpoint expression, such as programmed death ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3), with patient’s prognosis [5,6,7,8,9,10]. No combined immunoscore has been evaluated for prognostic stratification of early stage non-small-cell lung cancer (NSCLC). The main goal of this study was to investigate the prognostic impact of programmed death ligand 1 (PDL1) expression and different immune cell components (CD4+, CD8+ T-lymphocytes, and CD68+ macrophages) in early stage NSCLC patients, distinguishing peritumoral (PT) and intratumoral (IT) localizations. The secondary aim was to identify a combined immunoscore to optimize the prognostic stratification of NSCLC patients

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Results

Conclusion