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Programmed death-1 receptor (PD-1) and PD-ligand-1 (PD-L1) expression in non-small cell lung cancer and the immune-suppressive effect of anaerobic glycolysis

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Abstract

The microenvironment of a tumor may regulate the anti-tumor immune response. Intratumoral acidosis and hypoxia may suppress lymphocyte proliferation and migration, and this may have important implications in modern immunotherapy. The expression of PD-L1 by cancer cells and of PD-1 by tumor infiltrating lymphocytes (TILs) was assessed in tissue specimens from 98 operable NSCLC patients. Their prognostic role and their association with makers of glycolysis and anaerobic metabolism were assessed. Strong cytoplasmic/membrane PD-L1 expression was noted in 45/98 cases. Intense presence of TILs was noted in 42/98 cases (high TIL-score), and intense presence of PD-1 expressing TILs (high PIL-score) in 17/98 cases. PD-L1 expression was directly correlated with high PIL-score (p = 0.005). A significant inverse relationship was found between lactate dehydrogenase LDH5 expression and PIL-score (p = 0.008). Similarly, low PIL-score was significantly linked with high-hexokinase HXKII and monocarboxylate transporter MCT2 expression (p < 0.04). Cases with both intense TIL-score and PIL-score had significantly better survival (p < 0.05). For patients with high TIL-score or high PIL-score, PD-L1 overexpression defined significantly poorer survival (p = 0.01 and p = 0.03, respectively). In multivariate analysis, stage (p = 0.002, HR 3.33, 95%CI 1.4–4.5) and TIL-score (p = 0.02, HR 2.12, 95%CI 1.1–4.0) were independent predictive variables of death events. Given the low specificity of PD-L1 as a biomarker for anti-PD-1/PD-L1 immunotherapy, a combined assessment of TIL, PD-L1, PD-1, and LDH5 provides a tool for an immunological/metabolic classification of NSCLC tumors, with a different prognosis and different expected response to anti-PD-1/PD-L1 immunotherapy, which should be considered in relevant clinical trials.

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References

  1. Coley WB. The treatment of malignant tumors by repeated innoculations of erysipelas: with a report of ten original cases. Am J Med Sci. 1893;10:487–511.

    Article  Google Scholar 

  2. Bashford EF, Murray JA, Cramer W. The natural and induced resistance of mice to the growth of cancer. Proc R Soc B. 1907;79:164. https://doi.org/10.1098/rspb.1907.0014.

    Article  Google Scholar 

  3. Shi T, Ma Y, Yu L, Jiang J, Shen S, Hou Y, Wang T. Cancer immunotherapy: a focus on the regulation of immune checkpoints. Int J Mol Sci. 2018;2:89. https://doi.org/10.3390/ijms19051389.

    Article  CAS  Google Scholar 

  4. Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer. 2018;6:8.

    Article  Google Scholar 

  5. Leal TA, Ramalingam SS. Immunotherapy in previously treated non-small cell lung cancer (NSCLC). J Thorac Dis. 2018;10(Suppl 3):S422–32.

    Article  Google Scholar 

  6. Udall M, Rizzo M, Kenny J, Doherty J, Dahm S, Robbins P, Faulkner E. PD-L1 diagnostic tests: a systematic literature review of scoring algorithms and test-validation metrics. Diagn Pathol. 2018;13:12.

    Article  Google Scholar 

  7. Giatromanolaki A, Sivridis E, Arelaki S, Koukourakis MI. Expression of enzymes related to glucose metabolism in non-small cell lung cancer and prognosis. Exp Lung Res. 2017;43:167–74.

    Article  CAS  Google Scholar 

  8. Huber V, Camisaschi C, Berzi A, Ferro S, Lugini L, Triulzi T, Tuccitto A, Tagliabue E, Castelli C, Rivoltini. Cancer acidity: an ultimate frontier of tumor immune escape and a novel target of immunomodulation. Semin Cancer Biol. 2017;43:74–89.

    Article  CAS  Google Scholar 

  9. Damaghi M, Wojtkowiak JW, Gillies RJ. pH sensing and regulation in cancer. Front Physiol. 2013;4:370.

    Article  Google Scholar 

  10. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mulé JJ, Ibrahim-Hashim A, Gillies RJ. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 2016;76:1381–90.

    Article  CAS  Google Scholar 

  11. Karnik T, Kimler BF, Fan F, Tawfik O. PD-L1 in breast cancer: comparative analysis of 3 different antibodies. Hum Pathol. 2018;72:28–34.

    Article  CAS  Google Scholar 

  12. Schwert GW, Winer AD. Lactate dehydrogenase. In: Boyer PD, Lardy HA, Myrback K, editors. The enzymes, vol. 7. New York: Academic Press; 1963. p. 127–48.

    Google Scholar 

  13. Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumor-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer. 2011;105:93–103.

    Article  CAS  Google Scholar 

  14. Lin G, Fan X, Zhu W, Huang C, Zhuang W, Xu H, Lin X, Hu D, Huang Y, Jiang K, Miao Q, Li C. Prognostic significance of PD-L1 expression and tumor infiltrating lymphocyte in surgically resectable non-small cell lung cancer. Oncotarget. 2017;8:83986–94.

    PubMed  PubMed Central  Google Scholar 

  15. Feng W, Li Y, Shen L, Cai XW, Zhu ZF, Chang JH, Xiang JQ, Zhang YW, Chen HQ, Fu XL. Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer. Oncotarget. 2016;7:7227–40.

    PubMed  PubMed Central  Google Scholar 

  16. Horne ZD, Jack R, Gray ZT, Siegfried JM, Wilson DO, Yousem SA, Nason KS, Landreneau RJ, Luketich JD, Schuchert MJ. Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer. J Surg Res. 2011;171:1–5.

    Article  CAS  Google Scholar 

  17. Donnem T, Hald SM, Paulsen EE, Richardsen E, Al-Saad S, Kilvaer TK, Brustugun OT, Helland A, Lund-Iversen M, Poehl M, Olsen KE, Ditzel HJ, Hansen O, Al-Shibli K, Kiselev Y, Sandanger TM, Andersen S, Pezzella F, Bremnes RM, Busund LT. Stromal CD8+ T-cell density—a promising supplement to TNM staging in non-small cell lung cancer. Clin Cancer Res. 2015;21:2635–43.

    Article  Google Scholar 

  18. Zhuang X, Xia X, Wang C, Gao F, Shan N, Zhang L, Zhang L. A high number of CD8+ T cells infiltrated in NSCLC tissues is associated with a favorable prognosis. Appl Immunohistochem Mol Morphol. 2010;18:24–8.

    Article  Google Scholar 

  19. Kim MY, Koh J, Kim S, Go H, Jeon YK, Chung DH. Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: comparison with tumor-infiltrating T cells and the status of oncogenic drivers. Lung Cancer. 2015;88:24–33.

    Article  Google Scholar 

  20. Yan X, Jiao SC, Zhang GQ, Guan Y, Wang JL. Tumor-associated immune factors are associated with recurrence and metastasis in non-small cell lung cancer. Cancer Gene Ther. 2017;24:57–63.

    Article  CAS  Google Scholar 

  21. Kinoshita T, Muramatsu R, Fujita T, Nagumo H, Sakurai T, Noji S, Takahata E, Yaguchi T, Tsukamoto N, Kudo-Saito C, Hayashi Y, Kamiyama I, Ohtsuka T, Asamura H, Kawakami Y. Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer. Ann Oncol. 2016;27:2117–23.

    Article  CAS  Google Scholar 

  22. Chen YB, Mu CY, Huang JA. Clinical significance of programmed death-1 ligand-1 expression in patients with non-small cell lung cancer: a 5-year-follow-up study. Tumori. 2012;98:751–5.

    Article  Google Scholar 

  23. 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;94:107–16.

    Article  CAS  Google Scholar 

  24. Zhang Y, Wang L, Li Y, Pan Y, Wang R, Hu H, Li H, Luo X, Ye T, Sun Y, Chen H. Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma. Onco Targets Ther. 2014;7:567–73.

    Article  Google Scholar 

  25. Cooper WA, Tran T, Vilain RE, Madore J, Selinger CI, Kohonen-Corish M, Yip P, Yu B, O’Toole SA, McCaughan BC, Yearley JH, Horvath LG, Kao S, Boyer M, Scolyer RA. PD-L1 expression is a favorable prognostic factor in early-stage non-small cell carcinoma. Lung Cancer. 2015;89:181–8.

    Article  Google Scholar 

  26. Schmidt LH, Kümmel A, Görlich D, Mohr M, Bröckling S, Mikesch JH, Grünewald I, Marra A, Schultheis AM, Wardelmann E, Müller-Tidow C, Spieker T, Schliemann C, Berdel WE, Wiewrodt R, Hartmann W. PD-1 and PD-L1 expression in NSCLC indicate a favorable prognosis in defined subgroups. PLoS ONE. 2015;10:e0136023.

    Article  Google Scholar 

  27. Tokito T, Azuma K, Kawahara A, Ishii H, Yamada K, Matsuo N, Kinoshita T, Mizukami N, Ono H, Kage M, Hoshino T. Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer. 2016;55:7–14.

    Article  CAS  Google Scholar 

  28. Sun JM, Zhou W, Choi YL, Choi SJ, Kim SE, Wang Z, Dolled-Filhart M, Emancipator K, Wu D, Weiner R, Frisman D, Kim HK, Choi YS, Shim YM, Kim J. Prognostic significance of PD-L1 in patients with non-small cell lung cancer: a large cohort study of surgically resected cases. J Thorac Oncol. 2016;11:1003–11.

    Article  CAS  Google Scholar 

  29. Ameratunga M, Asadi K, Lin X, Walkiewicz M, Murone C, Knight S, Mitchell P, Boutros P, John T. PD-L1 and tumor infiltrating lymphocytes as prognostic markers in resected NSCLC. PLoS ONE. 2016;11:e0153954.

    Article  Google Scholar 

  30. Mori S, Motoi N, Ninomiya H, Matsuura Y, Nakao M, Mun M, Okumura S, Nishio M, Morikawa T, Ishikawa Y. High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild-type epidermal growth-factor receptor cases. Pathol Int. 2017;67:37–44.

    Article  CAS  Google Scholar 

  31. Okita R, Maeda A, Shimizu K, Nojima Y, Saisho S, Nakata M. PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer. Cancer Immunol Immunother. 2017;66:865–76.

    Article  CAS  Google Scholar 

  32. Wang K, Wang J, Wei F, Zhao N, Yang F, Ren X. Expression of TLR4 in non-small cell lung cancer is associated with PD-L1 and poor prognosis in patients receiving pulmonectomy. Front Immunol. 2017;8:456.

    Article  Google Scholar 

  33. Okuma Y, Hishima T, Kashima J, Homma S. High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer. Cancer Immunol Immunother. 2018;67:495–505.

    Article  CAS  Google Scholar 

  34. He Y, Rozeboom L, Rivard CJ, Ellison K, Dziadziuszko R, Yu H, Zhou C, Hirsch FR. PD-1, PD-L1 protein expression in non-small cell lung cancer and their relationship with tumor-infiltrating lymphocytes. Med Sci Monit. 2017;23:1208–16.

    Article  CAS  Google Scholar 

  35. Dovedi SJ, Illidge TM. The anti-tumor immune response generated by fractionated radiation therapy may be limited by tumor cell adaptive resistance and can be circumvented by PD-L1 blockade. Oncoimmunology. 2015;4(7):e1016709.

    Article  CAS  Google Scholar 

  36. Shen MJ, Xu LJ, Yang L, Tsai Y, Keng PC, Chen Y, Lee SO, Chen Y. Radiation alters PD-L1/NKG2D ligand levels in lung cancer cells and leads to immune escape from NK cell cytotoxicity via IL-6-MEK/Erk signaling pathway. Oncotarget. 2017;8(46):80506–20.

    PubMed  PubMed Central  Google Scholar 

  37. Shen X, Zhang L, Li J, Li Y, Wang Y, Xu ZX. Recent findings in the regulation of programmed death ligand 1 expression. Front Immunol. 2019;14(10):1337.

    Article  Google Scholar 

  38. Koukourakis MI, Giatromanolaki A. Warburg effect, lactate dehydrogenase and radio/chemo-therapy efficacy. Int J Radiat Biol. 2018;18:1–55.

    Google Scholar 

  39. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211:781–90.

    Article  CAS  Google Scholar 

  40. Schiltz PM, Dillman RO, Korse CM, Cubellis JM, Lee GJ, De Gast GC. Lack of elevation of serum S100B in patients with metastatic melanoma as a predictor of outcome after induction with an autologous vaccine of proliferating tumor cells and dendritic cells. Cancer Biother Radiopharm. 2008;23:214–21.

    Article  CAS  Google Scholar 

  41. Koukourakis MI, Giatromanolaki A, Bougioukas G, Sivridis E. Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol Ther. 2007;6:1476–9.

    Article  CAS  Google Scholar 

  42. Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E. Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res. 2006;66:632–7.

    Article  CAS  Google Scholar 

  43. Loeffler DA, Juneau PL, Masserant S. Influence of tumor physico-chemical conditions on interleukin-2 stimulated lymphocyte proliferation. Br J Cancer. 1992;66:619–22.

    Article  CAS  Google Scholar 

  44. Severin T, Muller B, Giese G, Uhl B, Wolf B, Hauschildt S, Kreutz W. pH-dependent LAK cell cytotoxicity. Tumor Biol. 1994;15:304–10.

    Article  CAS  Google Scholar 

  45. Loeffler DA, Juneau PL, Heppner GH. Natural killer cell activity under conditions reflective of tumor micro-environment. Int J Cancer. 1991;48:895–9.

    Article  CAS  Google Scholar 

  46. Redegeld F, Filippini A, Sitkovsky M. Comparative studies of the cytotoxic T lymphocyte-mediated cytotoxicity and of extracellular ATP-induced cell lysis. Different requirements in extracellular Mg1 and pH. J Immunol. 1991;147:3638–45.

    CAS  PubMed  Google Scholar 

  47. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M, Huber V, Parmiani G, Generoso L, Santinami M, Borghi M, Fais S, Bellone M, Rivoltini L. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 2012;72:2746–56.

    Article  CAS  Google Scholar 

  48. Bidani A, Wang CZ, Saggi SJ, Heming TA. Evidence for pH sensitivity of tumor necrosis factor-a release by alveolar macrophages. Lung. 1988;176:111–21.

    Article  Google Scholar 

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Funding

The study has been funded by the Tumour and Angiogenesis Research Group, Heraklion, Greece

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Authors and Affiliations

  1. Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece

    Alexandra Giatromanolaki & Konstantina Balaska

  2. Department of Radiotherapy/Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, PO Box 12, 68100, Alexandroupolis, Greece

    Ioannis M. Koukourakis, Achilleas G. Mitrakas & Michael I. Koukourakis

  3. Cancer Research UK, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    Adrian L. Harris

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  1. Alexandra Giatromanolaki
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  2. Ioannis M. Koukourakis
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Correspondence to Michael I. Koukourakis.

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The authors declare that they have no conflict of interest.

Ethical approval

Ethical approval was obtained from the Internal Scientific Committee and the Ethic Research Committee of the University Hospital of Alexandroupolis (study Approval Number ES11-26-11-18). The study was conducted according to the criteria set by the declaration of Helsinki.

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The study is retrospective on ‘existing holdings’ and no informed consent is demanded for examining anonymously archival material (material archived between 2002 and 2007). (Human Tissue Authority, E Research, Code of Practice and standards; https://www.hta.gov.uk/sites/default/files/Code%20E%20-%20Research%20Final.pdf; page 15, Consent exceptions paragraph 56 and 57).

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Giatromanolaki, A., Koukourakis, I.M., Balaska, K. et al. Programmed death-1 receptor (PD-1) and PD-ligand-1 (PD-L1) expression in non-small cell lung cancer and the immune-suppressive effect of anaerobic glycolysis. Med Oncol 36, 76 (2019). https://doi.org/10.1007/s12032-019-1299-4

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