Nalan AKYÜREK, Mehmet Ali Nahit ŞENDUR, Burak BİLGİN, Şebnem YÜCEL, Ülkü YILMAZ, Mutlu HIZAL, Bülent YALÇIN, Muhammed Bülent AKINCI

Küçük hücreli dışı akciğer kanserinde yüksek PD-L1 düzeyi ile ilişkili klinikopatolojik faktörlerin ve periferik kan parametrelerinin belirlenmesi

Giriş: “Programmed death ligand 1 (PD-L1)” immünoterapilere yanıtı predikte etmek için yaygın olarak kullanılan bir belirteçtir. Bununla birlikte PD-L1 düzeyinin dinamik değişimi gerçek zamanlı PD-L1 düzeyinin yansıtılması için büyük bir problemdir. Bu sebeple bu çalışmada akciğer kanseri tanısı olan hastalarda PD-L1 düzeyi ile ilişkili olabilecek faktörlerin saptanması amaçlanmıştır. Materyal ve Metod: Küçük hücreli dışı akciğer kanseri tanısı olan hastalar retrospektif olarak çalışmaya dahil edildi. Hastalar PD-L1 ekspresyon düzeyine göre < %50 ve ≥ %50 olmak üzere ikiye ayrıldı. Bulgular: Toplam 217 hasta çalışmaya dahil edildi. Her iki grubun sigara tüketimi dışında klinikopatolojik özellikleri benzerdi. PD-L1 düzeyi ≥ %50 olan grupta nötrofil lenfosit oranı, platelet lenfosit oranı ve sistemik immün inflamatuvar indeks anlamlı olarak daha düşük saptandı (sırasıyla; p< 0.001, p= 0.006 ve p= 0.003). Aynı zamanda bu parametreler PD-L1 ekspresyon düzeyi ile negatif korele olarak saptandı (sırasıyla, rho= -0.255, p< 0.001; rho= -0.17, p= 0.013; rho= -0.185, p= 0.006). Sonuç: Bizim çalışma sonuçlarımıza göre periferal kan parametreleri PD-L1 düzeyini predikte etmek için kullanılabilir ve böylece güncel PD-L1 ekspresyon düzeyi yansıtılabilir

The association of clinicopathologic features and peripheral blood parameters with high PD-L1 expression in non-small cell lung cancer

Introduction: Programmed death ligand 1 (PD-L1) is a marker that widelyused for prediction of response to immunotherapy. Dynamic alteration ofPD-L1 expression are the major problems for reflection of the actual status ofthe PD-L1. So, we aimed to investigate the factors that may be associated withPD-L1 expression in lung cancer.Materials and Methods: The patients diagnosed with non-small cell lung cancer were enrolled, retrospectively. The patients were stratified according toPD-L1 expression level as ≥ 50% and < 50%.Results: Totally, 217 patients were enrolled. The clinicopathologic featureswere similar between two groups, except the amount of cigarette consumption. Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and systemicimmune-inflammmotry index were found significantly lower in PD-L1 ≥ 50%(p< 0.001, p= 0.006 and p= 0.003, respectively) and also negatively correlated with PD-L1 level (rho= -0.255, p< 0.001; rho= -0.17, p= 0.013; rho= -0.185, p= 0.006, respectively)Conclusion: According to the results of our study, peripheral blood parameters can be used to the prediction of the high PD-L1expression and can be used for reflection of current PD-L1 expression.

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1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34.
2. Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med 2018;50:165.
3. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for firstline treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288-301.
4. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078-92.
5. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015;373:123-35.
6. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:1627-39.
7. Barlesi F, Vansteenkiste J, Spigel D, Ishii H, Garassino M, de Marinis F, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol 2018;19:1468-79.
8. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018;379:2342-50.
9. Shen X, Zhao B. Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis. BMJ 2018;362:k3529.
10. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.
11. Yi M, Jiao D, Xu H, Liu Q, Zhao W, Han X, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer 2018;17:129.
12. Kitano A, Ono M, Yoshida M, Noguchi E, Shimomura A, Shimoi T, et al. Tumour-infiltrating lymphocytes are correlated with higher expression levels of PD-1 and PD-L1 in early breast cancer. ESMO Open 2017;2:e000150
13. Chang LC, Chen TP, Kuo WK, Hua CC. The protein expression of PDL1 is highly correlated with those of eIF2alpha and ATF4 in lung cancer. Dis Markers 2018;2018:5068701.
14. Chen Y, Zhang Y, Chai X, Gao J, Chen G, Zhang W, et al. Correlation between the expression of PD-L1 and clinicopathological features in patients with thymic epithelial tumors. Biomed Res Int 2018;2018:5830547.
15. Teixido C, Vilarino N, Reyes R, Reguart N. PD-L1 expression testing in non-small cell lung cancer. Ther Adv Med Oncol 2018;10:1758835918763493.
16. Dietel M, Savelov N, Salanova R, Micke P, Bigras G, Hida T, et al. 130O Real-world prevalence of PD-L1 expression in locally advanced or metastatic non-small cell lung cancer (NSCLC): the global, multicentre EXPRESS study. J Thorac Oncol 2018;13:S74-S75.
17. Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, Gletzel-Plucinska N, Grzegrzolka J, et al. Role of PD-L1 expression in non-small cell lung cancer and their prognostic significance according to clinicopathological factors and diagnostic markers. Int J Mol Sci 2019;20.
18. Petrelli F, Maltese M, Tomasello G, Conti B, Borgonovo K, Cabiddu M, et al. Clinical and molecular predictors of PD-L1 expression in non-small-cell lung cancer: systematic review and meta-analysis. Clin Lung Cancer 2018;19:315- 22.
19. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in nonsmall cell lung cancer. Science 2015;348:124-8.
20. Mimura K, Teh JL, Okayama H, Shiraishi K, Kua LF, Koh V, et al. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci 2018;109:43-53.
21. Garcia-Diaz A, Shin DS, Moreno BH, Saco J, EscuinOrdinas H, Rodriguez GA, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression. Cell Rep 2017;19:1189-201.
22. Reed JM, Branigan PJ, Bamezai A. Interferon gamma enhances clonal expansion and survival of CD4+ T cells. J Interferon Cytokine Res 2008;28:611-22.
23. Yang R, Masters AR, Fortner KA, Champagne DP, YanguasCasas N, Silberger DJ, et al. IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21-producing B helper CD8+ T cells. J Exp Med 2016;213:2281-91.
24. Diem S, Schmid S, Krapf M, Flatz L, Born D, Jochum W, et al. Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-toLymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Lung Cancer 2017;111:176-81.
25. Bagley SJ, Kothari S, Aggarwal C, Bauml JM, Alley EW, Evans TL, et al. Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer. Lung Cancer 2017;106:1-7.
26. Moschetta M, Uccello M, Kasenda B, Mak G, McClelland A, Boussios S, et al. Dynamics of neutrophils-to-lymphocyte ratio predict outcomes of PD-1/PD-L1 blockade. Biomed Res Int 2017;2017:1506824.
27. Vilain RE, Menzies AM, Wilmott JS, Kakavand H, Madore J, Guminski A, et al. Dynamic changes in PD-L1 expression and immune infiltrates early during treatment predict response to PD-1 blockade in melanoma. Clin Cancer Res 2017;23:5024-33.