Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in non-small cell lung cancer

• Published in: PloS one Vol. 14; no. 5; p. e0216864
• Main Authors: Theelen, Willemijn S M E, Kuilman, Thomas, Schulze, Katja, Zou, Wei, Krijgsman, Oscar, Peters, Dennis D G C, Cornelissen, Sten, Monkhorst, Kim, Sarma, Pranamee, Sumiyoshi, Teiko, Amler, Lukas C, Willems, Stefan M, Blaauwgeers, Johannes L G, van Noesel, Carel J M, Peeper, Daniel S, van den Heuvel, Michel M, Kowanetz, Marcin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24-05-2019; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Aged, 80 and over; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Bioindicators; Biology and Life Sciences; Biomarkers; Cancer immunotherapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Classification; Female; Gene expression; Gene Expression Regulation, Neoplastic - immunology; Humans; Immune system; Immunity, Cellular; Immunohistochemistry; Immunology; Immunotherapy; Infiltration; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Ligands; Lung cancer; Lung diseases; Lung Neoplasms - genetics; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lymphocytes T; Male; Medical research; Medicine and Health Sciences; Metastases; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Neoplasm Staging; Non-small cell lung carcinoma; Oncology; Pathology; Patients; PD-1 protein; PD-L1 protein; Phenotypes; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Research and Analysis Methods; Signal Transduction - genetics; Signal Transduction - immunology; Signaling; Subgroups; Tumor cells; Tumor-infiltrating lymphocytes; Tumors; γ-Interferon; United States > US; Netherlands; South San Francisco California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0216864

In non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics.
Archival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell response was determined.
Tumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed.
These results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.