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

Overview

Journal Front Oncol

Specialty Oncology

Date 2020 Oct 19

PMID 33072595

Citations 5

Authors

Alice Boscolo

Francesco Fortarezza

Francesca Lunardi

Giovanni Comacchio

Loredana Urso

Stefano Frega

Jessica Menis

Laura Bonanno

Valentina Guarneri

Federico Rea

Pierfranco Conte

Fiorella Calabrese

Giulia Pasello

Affiliations

Soon will be listed here.

Abstract

Background: To 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.

Methods: This 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.

Results: Seventy-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, = 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 ( = 0.002).

Conclusion: The 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.

Citing Articles

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Genova C, Dellepiane C, Carrega P, Sommariva S, Ferlazzo G, Pronzato P Front Immunol. 2022; 12:799455.

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Hu C, Zhao L, Liu W, Fan S, Liu J, Liu Y J Immunother Cancer. 2021; 9(12).

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References

He Y, Yu H, Rozeboom L, Rivard C, Ellison K, Dziadziuszko R . LAG-3 Protein Expression in Non-Small Cell Lung Cancer and Its Relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes. J Thorac Oncol. 2017; 12(5):814-823. DOI: 10.1016/j.jtho.2017.01.019. View

Lin G, Fan X, Zhu W, Huang C, Zhuang W, Xu H . Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget. 2017; 8(48):83986-83994. PMC: 5663570. DOI: 10.18632/oncotarget.20233. View

Corredor G, Wang X, Zhou Y, Lu C, Fu P, Syrigos K . Spatial Architecture and Arrangement of Tumor-Infiltrating Lymphocytes for Predicting Likelihood of Recurrence in Early-Stage Non-Small Cell Lung Cancer. Clin Cancer Res. 2018; 25(5):1526-1534. PMC: 6397708. DOI: 10.1158/1078-0432.CCR-18-2013. View

Pasello G, Urso L, Mencoboni M, Grosso F, Ceresoli G, Lunardi F . MDM2 and HIF1alpha expression levels in different histologic subtypes of malignant pleural mesothelioma: correlation with pathological and clinical data. Oncotarget. 2015; 6(39):42053-66. PMC: 4747209. DOI: 10.18632/oncotarget.5974. View

Hendry S, Salgado R, Gevaert T, Russell P, John T, Thapa B . Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract.... Adv Anat Pathol. 2017; 24(6):311-335. PMC: 5638696. DOI: 10.1097/PAP.0000000000000161. View

Paulsen E, Kilvaer T, Rakaee Khanehkenari M, Maurseth R, Al-Saad S, Hald S . CD45RO(+) Memory T Lymphocytes--a Candidate Marker for TNM-Immunoscore in Squamous Non-Small Cell Lung Cancer. Neoplasia. 2015; 17(11):839-48. PMC: 4681889. DOI: 10.1016/j.neo.2015.11.004. View

Rakaee M, Rasmussen Busund L, Jamaly S, Paulsen E, Richardsen E, Andersen S . Prognostic Value of Macrophage Phenotypes in Resectable Non-Small Cell Lung Cancer Assessed by Multiplex Immunohistochemistry. Neoplasia. 2019; 21(3):282-293. PMC: 6369140. DOI: 10.1016/j.neo.2019.01.005. View

Takahashi Y, Kawamura M, Hato T, Harada M, Matsutani N, Horio H . Neutrophil-Lymphocyte Ratio as a Prognostic Marker for Lung Adenocarcinoma After Complete Resection. World J Surg. 2015; 40(2):365-72. DOI: 10.1007/s00268-015-3275-2. View

Hald S, Rakaee M, Martinez I, Richardsen E, Al-Saad S, Paulsen E . LAG-3 in Non-Small-cell Lung Cancer: Expression in Primary Tumors and Metastatic Lymph Nodes Is Associated With Improved Survival. Clin Lung Cancer. 2018; 19(3):249-259.e2. DOI: 10.1016/j.cllc.2017.12.001. View

10.

Teng F, Meng X, Wang X, Yuan J, Liu S, Mu D . Expressions of CD8+TILs, PD-L1 and Foxp3+TILs in stage I NSCLC guiding adjuvant chemotherapy decisions. Oncotarget. 2016; 7(39):64318-64329. PMC: 5325445. DOI: 10.18632/oncotarget.11793. View

11.

Donnem T, Kilvaer T, Andersen S, Richardsen E, Paulsen E, Hald S . Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol. 2015; 27(2):225-32. DOI: 10.1093/annonc/mdv560. View

12.

Donnem T, Hald S, Paulsen E, Richardsen E, Al-Saad S, Kilvaer T . Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer. Clin Cancer Res. 2015; 21(11):2635-43. DOI: 10.1158/1078-0432.CCR-14-1905. View

13.

Evans R, Diamond M, Rech A, Chao T, Richardson M, Lin J . Lack of immunoediting in murine pancreatic cancer reversed with neoantigen. JCI Insight. 2016; 1(14). PMC: 5026128. DOI: 10.1172/jci.insight.88328. View

14.

Lohinai Z, Bonanno L, Aksarin A, Pavan A, Megyesfalvi Z, Santa B . Neutrophil-lymphocyte ratio is prognostic in early stage resected small-cell lung cancer. PeerJ. 2019; 7:e7232. PMC: 6673426. DOI: 10.7717/peerj.7232. View

15.

Yang H, Shi J, Lin D, Li X, Zhao C, Wang Q . Prognostic value of PD-L1 expression in combination with CD8 TILs density in patients with surgically resected non-small cell lung cancer. Cancer Med. 2017; 7(1):32-45. PMC: 5773962. DOI: 10.1002/cam4.1243. View

16.

Owen D, Chaft J . Immunotherapy in surgically resectable non-small cell lung cancer. J Thorac Dis. 2018; 10(Suppl 3):S404-S411. PMC: 5861266. DOI: 10.21037/jtd.2017.12.93. View

17.

Angell H, Galon J . From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol. 2013; 25(2):261-7. DOI: 10.1016/j.coi.2013.03.004. View

18.

Galon J, Pages F, Marincola F, Angell H, Thurin M, Lugli A . Cancer classification using the Immunoscore: a worldwide task force. J Transl Med. 2012; 10:205. PMC: 3554496. DOI: 10.1186/1479-5876-10-205. View

19.

Rakaee M, Busund L, Paulsen E, Richardsen E, Al-Saad S, Andersen S . Prognostic effect of intratumoral neutrophils across histological subtypes of non-small cell lung cancer. Oncotarget. 2016; 7(44):72184-72196. PMC: 5342153. DOI: 10.18632/oncotarget.12360. View

20.

Detterbeck F, Boffa D, Kim A, Tanoue L . The Eighth Edition Lung Cancer Stage Classification. Chest. 2016; 151(1):193-203. DOI: 10.1016/j.chest.2016.10.010. View