Effect of platinum‑based chemotherapy on the expression of natural killer group 2 member D ligands, programmed cell death‑1 ligand 1 and HLA class I in non‑small cell lung cancer

• Published in: Oncology reports Vol. 42; no. 2; pp. 839 - 848
• Main Authors: Okita, Riki, Maeda, Ai, Shimizu, Katsuhiko, Nojima, Yuji, Saisho, Shinsuke, Nakata, Masao
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01-08-2019; Spandidos Publications UK Ltd
• Subjects: Aged; Antigens; Antineoplastic Agents - pharmacology; Apoptosis; B7-H1 Antigen - metabolism; Biochemistry; Biological response modifiers; Biomarkers, Tumor - metabolism; Cancer treatment; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; Cell Proliferation; Chemotherapy; Cisplatin - pharmacology; Clinical trials; Cloning; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Development and progression; Drug Resistance, Neoplasm - drug effects; Drug Therapy, Combination; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic - drug effects; GPI-Linked Proteins - metabolism; Histocompatibility Antigens Class I - metabolism; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - metabolism; Interferon; Interferon gamma; Investigations; Janus Kinases - antagonists & inhibitors; Killer cells; Killer Cells, Natural - drug effects; Ligands; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Middle Aged; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Non-small cell lung cancer; Patients; Pembrolizumab; Piperidines - pharmacology; Prognosis; Protein Kinase Inhibitors - pharmacology; Proteins; Pyrimidines - pharmacology; Pyrroles - pharmacology; Small cell lung cancer; Software industry; STAT Transcription Factors - antagonists & inhibitors; Surgery; T cells; Tofacitinib; Tumor Cells, Cultured; Tumors; United States; Japan; United States > US
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2019.7185

Platinum‑based chemotherapy improves the clinical outcome of patients with non‑small cell lung cancer (NSCLC), although tumors often become refractory after treatment. Immunohistochemical staining was performed to investigate the expression levels of natural killer group 2 member D (NKG2D) ligands, programmed cell death‑1 ligand 1 (PD‑L1), and human leucocyte antigen (HLA)‑class I in tissue samples collected from 10 NSCLC patients who received platinum‑based chemotherapy followed by surgery. Additionally, the effects of repeated exposure to cisplatin on the expression of NKG2D ligands, PD‑L1 and HLA‑class I in NSCLC cell lines were assessed by flow cytometry. We found upregulation of PD‑L1 or downregulation of NKG2D ligands in 5 of the 10 NSCLC cases, leading to the attenuation of NK cell‑mediated tumor cell death. Moreover, upregulation of PD‑L1 or downregulation of HLA‑class I were observed in 6 cases, supporting tumor escape from T cell immunity. An in vitro assay showed that repeated exposure to cisplatin enhanced the expression of PD‑L1 and NKG2D ligands in NSCLC cell lines. Notably, interferon gamma (IFNγ) stimuli enhanced PD‑L1 expression while attenuated that of NKG2D ligands in NSCLC cell lines, which mimicked the results of the clinical study. Both IFNγ‑induced upregulation of PD‑L1 and downregulation of NKG2D ligands were blocked by the JAK‑STAT inhibitor tofacitinib. These findings suggested that the expression levels of NKG2D ligands, PD‑L1 and HLA‑class I in residual tumors after chemotherapy were affected by host immunity, resulting in an immunoescape phenotype. Blocking IFNγ‑induced tumor immunoescape by a JAK‑STAT inhibitor might be a promising treatment strategy for NSCLC.