Prognostic significance of programmed death-1 and programmed death-ligand 1 expression in patients with esophageal squamous cell carcinoma

Kaiyan Chen, Guoping Cheng, Fanrong Zhang, Nan Zhang, Dan Li, Jiaoyue Jin, Junzhou Wu, Lisha Ying, Weimin Mao, Dan Su, Kaiyan Chen, Guoping Cheng, Fanrong Zhang, Nan Zhang, Dan Li, Jiaoyue Jin, Junzhou Wu, Lisha Ying, Weimin Mao, Dan Su

Abstract

Aims: To evaluate the expression of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) and their clinical and prognostic significance in primary esophageal squamous cell carcinoma (ESCC).

Results: The expression rate of PD-1 and PD-L1 in ESCC was 33.5% (117/349) and 41.4% (222/536), respectively. PD-L1 expression differed significantly by tumor location, grade, lymph node metastases, and disease stage (P < 0.05). Moreover, its expression was associated with the disease free survival (DFS). Patients with positive PD-L1 expression had reduced risk for disease relapse compared to those without PD-L1 expression (Hazard ratio [HR] = 0.75, 95% confidence interval [CI]: 0.56-1.00, P = 0.048). Kaplan-Meier curves showed the similar result, P = 0.047. However, there was no significant correlation between PD-1 expression and clinicopathological factors or outcome in ESCC (P > 0.05).

Methods: The expression of PD-1 and PD-L1 was assessed by immunohistochemistry on tissue microarrays from 536 primary ESCC who underwent surgery during January 2008 and April 2012 in Zhejiang Cancer Hospital. Chi-square test and Cox proportional hazards regression were employed to analyze the associations between their expressions and clinicopathological variables and survival.

Conclusions: Our results suggested that PD-L1 could be a favorable indicator of prognosis in ESCC.

Keywords: PD-1; PD-L1; esophageal cancer; immunochemistry; prognosis.

Conflict of interest statement

No potential conflicts of interest were disclosed.

Figures

Figure 1. PD-1 and PD-L1 expression in…
Figure 1. PD-1 and PD-L1 expression in ESCC by immunohistochemistry staining
(A) Negative expression of PD-L1. (B) Positive expression of PD-L1. (C) Negative expression of PD-1. (D) Positive expression of PD-1. Original magnification ×200.
Figure 2. Kaplan-Meier curves of DFS and…
Figure 2. Kaplan-Meier curves of DFS and OS in ESCC based upon PD-1 and PD-L1 expression
Patients with PD-L1 expression had significantly longer DFS than those without PD-L1 expression (median DFS: not reached verse 41.3 months, P = 0.047, (A). There was no statistically significant difference in OS between the patients with positive and negative PD-L1 staining (median OS: 57.6 verse 41.3 months, P = 0.218, (B). PD-1 expression was not significantly correlated with DFS or OS in ESCC (P > 0.05, (C and D).

References

    1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;24:2137–2150.
    1. Song Y, Li L, Ou Y, Gao Z, Li E, Li X, Zhang W, Wang J, Xu L, Zhou Y, Ma X, Liu L, Zhao Z, et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature. 2014;509:91–95.
    1. Xu Y, Yu X, Chen Q, Mao W. Neoadjuvant versus adjuvant treatment: which one is better for resectable esophageal squamous cell carcinoma? World J Surg Oncol. 2012;10:173.
    1. 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, 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.
    1. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–2454.
    1. Derks S, Nason KS, Liao X, Stachler MD, Liu KX, Liu JB, Sicinska E, Goldberg MS, Freeman GJ, Rodig SJ, Davison JM, Bass AJ. Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma. Cancer Immunol Res. 2015;3:1123–1129.
    1. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. 2002;2:116–126.
    1. Mkrtichyan M, Najjar YG, Raulfs EC, Abdalla MY, Samara R, Rotem-Yehudar R, Cook L, Khleif SN. Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Eur J Immunol. 2011;41:2977–2986.
    1. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–212.
    1. Reiss KA, Forde PM, Brahmer JR. Harnessing the power of the immune system via blockade of PD-1 and PD-L1: a promising new anticancer strategy. Immunotherapy. 2014;6:459–475.
    1. Xu F, Xu L, Wang Q, An G, Feng G, Liu F. Clinicopathological and prognostic value of programmed death ligand-1 (PD-L1) in renal cell carcinoma: a meta-analysis. Int J Clin Exp Med. 2015;8:14595–14603.
    1. Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res. 2015;21:976–984.
    1. Qing Y, Li Q, Ren T, Xia W, Peng Y, Liu GL, Luo H, Yang YX, Dai XY, Zhou SF, Wang D. Upregulation of PD-L1 and APE1 is associated with tumorigenesis and poor prognosis of gastric cancer. Drug Des Devel Ther. 2015;9:901–909.
    1. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–2465.
    1. Sui X, Ma J, Han W, Wang X, Fang Y, Li D, Pan H, Zhang L. The anticancer immune response of anti-PD-1/PD-L1 and the genetic determinants of response to anti-PD-1/PD-L1 antibodies in cancer patients. Oncotarget. 2015;6:19393–19404. doi: 10.18632/oncotarget.5107.
    1. Zhang Y, Kang S, Shen J, He J, Jiang L, Wang W, Guo Z, Peng G, Chen G, He J, Liang W. Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) Expression in epithelial-originated cancer: a meta-analysis. Medicine (Baltimore) 2015;94:e515.
    1. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016;47:78–84.
    1. Thierauf J, Veit JA, Affolter A, Bergmann C, Grunow J, Laban S, Lennerz JK, Grunmuller L, Mauch C, Plinkert PK, Hess J, Hoffmann TK. Identification and clinical relevance of PD-L1 expression in primary mucosal malignant melanoma of the head and neck. Melanoma Res. 2015;25:503–509.
    1. Liu Y, Carlsson R, Ambjorn M, Hasan M, Badn W, Darabi A, Siesjo P, Issazadeh-Navikas S. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. J Neurosci. 2013;33:14231–14245.
    1. Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, Budczies J, Bockmayr M, Dietel M, Denkert C, Braicu I, Johrens K. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget. 2016;7:1486–99. doi: 10.18632/oncotarget.6429.
    1. Chen L, Deng H, Lu M, Xu B, Wang Q, Jiang J, Wu C. B7-H1 expression associates with tumor invasion and predicts patient's survival in human esophageal cancer. Int J Clin Exp Pathol. 2014;7:6015–6023.
    1. Huang B, Chen L, Bao C, Sun C, Li J, Wang L, Zhang X. The expression status and prognostic significance of programmed cell death 1 ligand 1 in gastrointestinal tract cancer: a systematic review and meta-analysis. Onco Targets Ther. 2015;8:2617–2625.
    1. Droeser RA, Hirt C, Viehl CT, Frey DM, Nebiker C, Huber X, Zlobec I, Eppenberger-Castori S, Tzankov A, Rosso R, Zuber M, Muraro MG, Amicarella F, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 2013;49:2233–2242.
    1. Loos M, Langer R, Schuster T, Gertler R, Walch A, Rauser S, Friess H, Feith M. Clinical significance of the costimulatory molecule B7-H1 in Barrett carcinoma. Ann Thorac Surg. 2011;91:1025–1031.
    1. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra137.
    1. Velcheti V, Schalper KA, Carvajal DE, Anagnostou VK, Syrigos KN, Sznol M, Herbst RS, Gettinger SN, Chen L, Rimm DL. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest. 2014;94:107–116.
    1. Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL. In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res. 2014;20:2773–2782.
    1. Schmidt LH, Kummel A, Gorlich D, Mohr M, Brockling S, Mikesch JH, Grunewald I, Marra A, Schultheis AM, Wardelmann E, Muller-Tidow C, Spieker T, Schliemann C, et al. PD-1 and PD-L1 Expression in NSCLC Indicate a Favorable Prognosis in Defined Subgroups. PLoS One. 2015;10:e0136023.
    1. Wang S, Bajorath J, Flies DB, Dong H, Honjo T, Chen L. Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction. J Exp Med. 2003;197:1083–1091.
    1. Subudhi SK, Zhou P, Yerian LM, Chin RK, Lo JC, Anders RA, Sun Y, Chen L, Wang Y, Alegre ML, Fu YX. Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J Clin Invest. 2004;113:694–700.
    1. 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.
    1. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116.
    1. Liu J, Li F, Ping Y, Wang L, Chen X, Wang D, Cao L, Zhao S, Li B, Kalinski P, Thorne SH, Zhang B, Zhang Y. Local production of the chemokines CCL5 and CXCL10 attracts CD8+ T lymphocytes into esophageal squamous cell carcinoma. Oncotarget. 2015;6:24978–24989. doi: 10.18632/oncotarget.4617.
    1. 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.
    1. D'Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, Tibaldi C, Minuti G, Salvini J, Coppi E, Chella A, Fontanini G, Filice ME, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112:95–102.

Source: PubMed

3
Subscribe