The role of PD-L1 in the radiation response and prognosis for esophageal squamous cell carcinoma related to IL-6 and T-cell immunosuppression
Miao-Fen Chen, Ping-Tsung Chen, Wen-Cheng Chen, Ming-Shian Lu, Paul-Yang Lin, Kuan Der Lee, Miao-Fen Chen, Ping-Tsung Chen, Wen-Cheng Chen, Ming-Shian Lu, Paul-Yang Lin, Kuan Der Lee
Abstract
The aim of this study was to assess the significance of programmed cell death 1 ligand 1 (PD-L1) in esophageal squamous cell carcinoma (ESCC) and its association with IL-6 and radiation response. Weretrospectively enrolled 162 patients with ESCC, and examined the correlation between PD-L1 levels and clinical outcomes in esophageal cancer patients. Furthermore, the human esophageal SCC cell line CE81T and TE2 were selected for cellular experiments to investigate the role of PD-L1 in T cell functions and radiation response. Here we demonstrated that PD-L1 expression was significantly higher in esophageal cancer specimens than in non-malignant epithelium. In clinical outcome analysis, this staining of PD-L1 was positively linked to the clinical T4 stage (p=0.004), development of LN metastasis (p=0.012) and higher loco-regional failure rate (p=0.0001). In addition, the frequency of PD-L1 immunoreactivity was significantly higher in IL-6-positive esophageal cancer specimens. When IL-6 signaling was inhibited in vitro, the level of PD-L1 is significantly down-regulated. PD-L1 is a significant predictor for poor treatment response and shorter survival.As demonstrated through in vitro experiments, Irradiation increased PD-L1 expression in human esophageal cancer cells. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells might be the mechanisms responsible to the role of PD-L1 in radiation response. In conclusion, PD-L1 is important in determining the radiation response and could predict the prognosis of patients with esophageal SCC. Therefore, we suggest inhibition of PD-L1 as a potential strategy for the treatment of esophageal SCC.
Keywords: CD8+ T cell; IL-6; PD-L1; esophageal SCC.
Conflict of interest statement
CONFLICTS OF INTEREST
The authors confirm that there are no conflicts of interest that could be perceived as prejudicing the impartiality of the research reported.
Figures
References
- Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–2252.
- Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–692.
- Pottgen C, Stuschke M. Radiotherapy versus surgery within multimodality protocols for esophageal cancer--a meta-analysis of the randomized trials. Cancer Treat Rev. 2012;38:599–604.
- Schoenfeld JD. Immunity in head and neck cancer. Cancer Immunol Res. 2015;3:12–17.
- Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of immunotherapy and radiation in cancer therapy. Front Oncol. 2014;4:325.
- Noh H, Hu J, Wang X, Xia X, Satelli A, Li S. Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells. Cell Commun Signal. 2015;13:14.
- Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293–12297.
- Afreen S, Dermime S. The immunoinhibitory B7-H1 molecule as a potential target in cancer: killing many birds with one stone. Hematol Oncol Stem Cell Ther. 2014;7:1–17.
- Pilones KA, Vanpouille-Box C, Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin Radiat Oncol. 2015;25:28–33.
- Ritprajak P, Azuma M. Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD-L1 in epithelial cells and squamous cell carcinoma. Oral Oncol. 2015;51:221–228.
- Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454:436–444.
- Vakkila J, Lotze MT. Inflammation and necrosis promote tumour growth. Nat Rev Immunol. 2004;4:641–648.
- Chen MF, Chen PT, Lu MS, Lin PY, Chen WC, Lee KD. IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer. 2013;12:26.
- Hu CP, Hsieh HG, Chien KY, Wang PY, Wang CI, Chen CY, Lo SJ, Wuu KD, Chang CM. Biologic properties of three newly established human esophageal carcinoma cell lines. J Natl Cancer Inst. 1984;72:577–583.
- Li SH, Huang EY, Lu HI, Huang WT, Yen CC, Huang WC, Chen CH. Phosphorylated mammalian target of rapamycin expression is associated with the response to chemoradiotherapy in patients with esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2012;144:1352–1359. 1359 e1351.
- Chen PT, Hsieh CC, Wu CT, Yen TC, Lin PY, Chen WC, Chen MF. 1alpha,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling. Mol Cancer Ther. 2015;14:1365–1375.
- Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and Survival in Solid Tumors: A Meta-Analysis. PLoS One. 2015;10:e0131403.
- Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947–2953.
- Maine CJ, Aziz NH, Chatterjee J, Hayford C, Brewig N, Whilding L, George AJ, Ghaem-Maghami S. Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer. Cancer Immunol Immunother. 2014;63:215–224.
- Zhang Y, Li J, Lou J, Zhou Y, Bo L, Zhu J, Zhu K, Wan X, Cai Z, Deng X. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care. 2011;15:R70.
- Xu P, Zhang P, Sun Z, Wang Y, Chen J, Miao C. Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway. Cancer Immunol Immunother. 2015;64:1383–1392.
- Geng L, Jiang G, Fang Y, Dong S, Xie H, Chen Y, Shen M, Zheng S. B7-H1 expression is upregulated in peripheral blood CD14+ monocytes of patients with chronic hepatitis B virus infection, which correlates with higher serum IL-10 levels. J Viral Hepat. 2006;13:725–733.
- Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA, Fauci AS. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181:6738–6746.
- Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7:651–658.
- Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA, Wasik MA. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1) Proc Natl Acad Sci U S A. 2008;105:20852–20857.
- Schafer ZT, Brugge JS. IL-6 involvement in epithelial cancers. J Clin Invest. 2007;117:3660–3663.
- Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine. Adv Immunol. 1993;54:1–78.
- Chen CC, Chen WC, Lu CH, Wang WH, Lin PY, Lee KD, Chen MF. Significance of interleukin-6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor. Int J Radiat Oncol Biol Phys. 2010;76:1214–1224.
- Santer FR, Malinowska K, Culig Z, Cavarretta IT. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr Relat Cancer. 2010;17:241–253.
- Chen MF, Kuan FC, Yen TC, Lu MS, Lin PY, Chung YH, Chen WC, Lee KD. IL-6-stimulated CD11b+ CD14+ HLA-DR- myeloid-derived suppressor cells, are associated with progression and poor prognosis in squamous cell carcinoma of the esophagus. Oncotarget. 2014;5:8716–28. doi: 10.18632/oncotarget.2368.
- Yoneda M, Fujiwara H, Furutani A, Ikai A, Tada H, Shiozaki A, Komatsu S, Kubota T, Ichikawa D, Okamoto K, Konishi H, Murayama Y, Kuriu Y, et al. Prognostic impact of tumor IL-6 expression after preoperative chemoradiotherapy in patients with advanced esophageal squamous cell carcinoma. Anticancer Res. 2013;33:2699–705.
- Fujiwara H1, Suchi K, Okamura S, Okamura H, Umehara S, Todo M, Shiozaki A, Kubota T, Ichikawa D, Okamoto K, Ochiai T, Kokuba Y, Sonoyama T, et al. Elevated serum CRP levels after induction chemoradiotherapy reflect poor treatment response in association with IL-6 in serum and local tumor site in patients with advanced esophageal cancer. J Surg Oncol. 2011;103:62–8.
- Leu CM, Wong FH, Chang C, Huang SF, Hu CP. Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene. 2003;22:7809–7818.
- Toomey PG, Vohra NA, Ghansah T, Sarnaik AA, Pilon-Thomas SA. Immunotherapy for gastrointestinal malignancies. Cancer Control. 2013;20:32–42.
- Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with metaanalysis. Br J Cancer. 2011;105:93–103.
- Nosho K, Baba Y, Tanaka N, Shima K, Hayashi M, Meyerhardt JA, Giovannucci E, Dranoff G, Fuchs CS, Ogino S. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol. 2010;222:350–366.
- M undy-Bosse BL, Young GS, Bauer T, Binkley E, Bloomston M, Bill MA, Bekaii-Saab T, Carson WE, 3rd, Lesinski GB. Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferonalpha signaling in CD4+ T cells from patients with GI malignancy. Cancer Immunol Immunother. 2011;60:1269–1279.
- Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, Hida Y, Oshikiri T, Kurokawa T, Suzuoki M, Nakakubo Y, Hiraoka K, Murakami S, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res. 2003;63:1555–1559.
- Schumacher K, Haensch W, Roefzaad C, Schlag PM. Prognostic significance of activated CD8(+) T cell infiltrations within esophageal carcinomas. Cancer Res. 2001;61:3932–3936.
- Lu B, Chen L, Liu L, Zhu Y, Wu C, Jiang J, Zhang X. T-cell-mediated tumor immune surveillance and expression of B7 co-inhibitory molecules in cancers of the upper gastrointestinal tract. Immunol Res. 2011;50:269–75.
- Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–6587.
- Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–499.
- Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–264.
Source: PubMed