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

Okita,Riki; Maeda,Ai; Shimizu,Katsuhiko; Nojima,Yuji; Saisho,Shinsuke; Nakata,Masao

doi:10.3892/or.2019.7185

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

Authors:
- Riki Okita
- Ai Maeda
- Katsuhiko Shimizu
- Yuji Nojima
- Shinsuke Saisho
- Masao Nakata
View Affiliations

Affiliations: Department of General Thoracic Surgery, Kawasaki Medical School, Kurashiki 701‑0192, Japan
Published online on: June 3, 2019 https://doi.org/10.3892/or.2019.7185
Pages: 839-848

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Baggstrom MQ, Stinchcombe TE, Fried DB, Poole C, Hensing TA and Socinski MA: Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: A meta-analysis. J Thorac Oncol. 2:845–853. 2007. View Article : Google Scholar : PubMed/NCBI
3	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
4	Lanier LL: A renaissance for the tumor immunosurveillance hypothesis. Nat Med. 7:1178–1180. 2001. View Article : Google Scholar : PubMed/NCBI
5	Ljunggren HG and Malmberg KJ: Prospects for the use of NK cells in immunotherapy of human cancer. Nat Rev Immunol. 7:329–339. 2007. View Article : Google Scholar : PubMed/NCBI
6	Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL and Spies T: Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 285:727–729. 1999. View Article : Google Scholar : PubMed/NCBI
7	Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL and Phillips JH: An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 285:730–732. 1999. View Article : Google Scholar : PubMed/NCBI
8	Ogasawara K and Lanier LL: NKG2D in NK and T cell-mediated immunity. J Clin Immunol. 25:534–540. 2005. View Article : Google Scholar : PubMed/NCBI
9	Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M and Chalupny NJ: ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity. 14:123–133. 2001. View Article : Google Scholar : PubMed/NCBI
10	Groh V, Bahram S, Bauer S, Herman A, Beauchamp M and Spies T: Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA. 93:12445–12450. 1996. View Article : Google Scholar : PubMed/NCBI
11	Bryceson YT, March ME, Ljunggren HG and Long EO: Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev. 214:73–91. 2006. View Article : Google Scholar : PubMed/NCBI
12	Gasser S, Orsulic S, Brown EJ and Raulet DH: The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 436:1186–1190. 2005. View Article : Google Scholar : PubMed/NCBI
13	Tolis C, Peters GJ, Ferreira CG, Pinedo HM and Giaccone G: Cell cycle disturbances and apoptosis induced by topotecan and gemcitabine on human lung cancer cell lines. Eur J Cancer. 35:796–807. 1999. View Article : Google Scholar : PubMed/NCBI
14	Okita R, Yukawa T, Nojima Y, Maeda A, Saisho S, Shimizu K and Nakata M: MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer. Cancer Immunol Immunother. 65:499–509. 2016. View Article : Google Scholar : PubMed/NCBI
15	Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, et al: Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 192:1027–1034. 2000. View Article : Google Scholar : PubMed/NCBI
16	Blank C, Gajewski TF and Mackensen A: Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: Implications for tumor immunotherapy. Cancer Immunol Immunother. 54:307–314. 2005. View Article : Google Scholar : PubMed/NCBI
17	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
18	Peng J, Hamanishi J, Matsumura N, Abiko K, Murat K, Baba T, Yamaguchi K, Horikawa N, Hosoe Y, Murphy SK, et al: Chemotherapy induces programmed cell death-ligand 1 overexpression via the nuclear factor-κB to Foster an Immunosuppressive tumor microenvironment in ovarian cancer. Cancer Res. 75:5034–5045. 2015. View Article : Google Scholar : PubMed/NCBI
19	Katsuya Y, Horinouchi H, Asao T, Kitahara S, Goto Y, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Watanabe S, et al: Expression of programmed death 1 (PD-1) and its ligand (PD-L1) in thymic epithelial tumors: Impact on treatment efficacy and alteration in expression after chemotherapy. Lung Cancer. 99:4–10. 2016. View Article : Google Scholar : PubMed/NCBI
20	Rojkó L, Reiniger L, Téglási V, Fábián K, Pipek O, Vágvölgyi A, Agócs L, Fillinger J, Kajdácsi Z, Tímár J, et al: Chemotherapy treatment is associated with altered PD-L1 expression in lung cancer patients. J Cancer Res Clin Oncol. 144:1219–1226. 2018. View Article : Google Scholar : PubMed/NCBI
21	Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, et al: Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 378:2078–2092. 2018. View Article : Google Scholar : PubMed/NCBI
22	Travis WD, Brambilla E, Müller-Hermelink HK and Harris CC: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARCPress; Lyon: 2004
23	Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, et al: International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 6:244–285. 2011. View Article : Google Scholar : PubMed/NCBI
24	Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, Postmus PE, Rusch V and Sobin L; International Association for the Study of Lung Cancer International Staging Committ, : The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2:706–714. 2007. View Article : Google Scholar : PubMed/NCBI
25	Okita R, Wolf D, Yasuda K, Maeda A, Yukawa T, Saisho S, Shimizu K, Yamaguchi Y, Oka M, Nakayama E, et al: Contrasting effects of the cytotoxic anticancer drug gemcitabine and the EGFR tyrosine kinase inhibitor gefitinib on NK cell-mediated cytotoxicity via regulation of NKG2D ligand in non-small-cell lung cancer cells. PLoS One. 10:e01398092015. View Article : Google Scholar : PubMed/NCBI
26	Vermorken JB, van der Vijgh WJ, Klein I, Gall HE, van Groeningen CJ, Hart GA and Pinedo HM: Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of cisplatin. Clin Pharmacol Ther. 39:136–144. 1986. View Article : Google Scholar : PubMed/NCBI
27	Okita R, Mougiakakos D, Ando T, Mao Y, Sarhan D, Wennerberg E, Seliger B, Lundqvist A, Mimura K and Kiessling R: HER2/HER3 signaling regulates NK cell-mediated cytotoxicity via MHC class I chain-related molecule A and B expression in human breast cancer cell lines. J Immunol. 188:2136–2145. 2012. View Article : Google Scholar : PubMed/NCBI
28	Yamaguchi K, Chikumi H, Shimizu A, Takata M, Kinoshita N, Hashimoto K, Nakamoto M, Matsunaga S, Kurai J, Miyake N, et al: Diagnostic and prognostic impact of serum-soluble UL16-binding protein 2 in lung cancer patients. Cancer Sci. 103:1405–1413. 2012. View Article : Google Scholar : PubMed/NCBI
29	Zitvogel L, Galluzzi L, Kepp O, Smyth MJ and Kroemer G: Type I interferons in anticancer immunity. Nat Rev Immunol. 15:405–414. 2015. View Article : Google Scholar : PubMed/NCBI
30	Schwinn N, Vokhminova D, Sucker A, Textor S, Striegel S, Moll I, Nausch N, Tuettenberg J, Steinle A, Cerwenka A, et al: Interferon-gamma down-regulates NKG2D ligand expression and impairs the NKG2D-mediated cytolysis of MHC class I-deficient melanoma by natural killer cells. Int J Cancer. 124:1594–1604. 2009. View Article : Google Scholar : PubMed/NCBI
31	Shimizu K, Okita R, Saisho S, Maeda AI, Nojima Y and Nakata M: Impact of COX2 inhibitor for regulation of PD-L1 expression in non-small cell lung cancer. Anticancer Res. 38:4637–4644. 2018. View Article : Google Scholar : PubMed/NCBI
32	Cancer Genome Atlas Research Network, . Comprehensive molecular profiling of lung adenocarcinoma. Nature. 511:543–550. 2014. View Article : Google Scholar : PubMed/NCBI
33	Akbay EA, Koyama S, Carretero J, Altabef A, Tchaicha JH, Christensen CL, Mikse OR, Cherniack AD, Beauchamp EM, Pugh TJ, et al: Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 3:1355–1363. 2013. View Article : Google Scholar : PubMed/NCBI
34	Ota K, Azuma K, Kawahara A, Hattori S, Iwama E, Tanizaki J, Harada T, Matsumoto K, Takayama K, Takamori S, et al: Induction of PD-L1 expression by the EML4-ALK oncoprotein and downstream signaling pathways in non-small cell lung cancer. Clin Cancer Res. 21:4014–4021. 2015. View Article : Google Scholar : PubMed/NCBI