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PD-L1 Expression on Lung Cancer Stem Cells in Metastatic Lymph Nodes Aspirates

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Abstract

Objectives

An immunotherapy was found to be effective in achieving long-term survival in some lung cancer patients. It has emerged to searching for new immune biomarkers for select the best candidates to this therapy. It is suggested that cancer stem cells (CSCs) are responsible for tumor initiation, maintenance and its metastatic potential. However, a role of CSCs in escape of cancer from immunosurveillance is unknown. The aim of the study was assess the phenotype of putative CSCs and to examine the expression of PD-L1 on CSCs in metastatic lymph nodes (LNs) in lung cancer patients.

Material and Methods

Flow cytometry was used for CSCs evaluation in peripheral blood and EBUS/TBNA aspirates from N1,N2 lymph nodes in lung cancer patients.

Results

Of 30 patients the LNs metastases were confirmed in 18 patients. We noticed presence of PD-L1 on putative lung CSCs- CD133 + EpCAM+ cells. A higher percentage of CD133 + EpCAM+PD-L1+ cells was observed in patients with metastatic in LNs- median value = 4.38% than in patients without LNs metastases– median value = 0,015% (p < 0.05). The highest proportion of PD-L1+ CSCs was found in adenocarcinoma patients and in those with oncogene addiction what indicate an particular biology of this type of lung cancer.

Conclusion

The presence of CSCs with expression of PD-L1 in the metastatic LNs might suggest their immunogenic potential. EBUS/TBNA is commonly used in diagnosis and staging of lung cancer, so the analysis of the cells in metastatic LNs may fit in “immunoscoring” before immunotherapy.

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References

  1. http://gco.iarc.fr. Accessed 6 Oct 2018.

  2. Ogino, S., Galon, J., Fuchs, C. S., & Dranoff, G. (2011). Cancer immunology-analysis of host and tumor factors for personalized medicine. Nature Reviews. Clinical Oncology, 8(12), 711–719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Domagala-Kulawik, J., Kwiecien, I., Pankowski, J., et al. (2017). Elevated Foxp3/CD8 ratio in lung adenocarcinoma metastatic lymph nodes resected by transcervical extended mediastinal lymphadenectomy. BioMed Research International, 5185034. https://doi.org/10.1155/2017/5185034.

  4. Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., Miller, M. L., Rekhtman, N., Moreira, A. L., Ibrahim, F., Bruggeman, C., Gasmi, B., Zappasodi, R., Maeda, Y., Sander, C., Garon, E. B., Merghoub, T., Wolchok, J. D., Schumacher, T. N., & Chan, T. A. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science, 348, 124–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sun, J. M., Zhou, W., Choi, Y. L., Choi, S. J., Kim, S. E., Wang, Z., Dolled-Filhart, M., Emancipator, K., Wu, D., Weiner, R., Frisman, D., Kim, H. K., Choi, Y. S., Shim, Y. M., & Kim, J. (2016). Prognostic significance of PD-L1 in patients with non-small cell lung cancer: a large cohort study of surgically resected cases. Journal of Thoracic Oncology, 11, 1003–1011.

    Article  CAS  PubMed  Google Scholar 

  6. Regenbrecht, C. R. A., Lehrach, H., & Adjaye, J. (2008). Stemming cancer: functional genomics of cancer stem cells in solid tumors. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-008-9034-0.

  7. Vermeulen, L., de Sousa e Melo, F., Richel, D. J., & Medema, J. P. (2012). The developing cancer stem-cell model: clinical challenges and opportunities. Lancet Oncology, 13, 83–89.

    Article  Google Scholar 

  8. Sales, K. M., Winslet, M. C., & Seifalian, A. M. (2007). Stem cells and cancer: an overview. Stem Cell Reviews and Reports. https://doi.org/10.1007/s12015-007-9002-0.

  9. Yu, S., & Bian, X. (2009). Enrichment of Cancer stem cells based on heterogeneity of invasiveness. Stem Cell Reviews and Reports, 5, 66–71. https://doi.org/10.1007/s12015-008-9047-8.

    Article  CAS  PubMed  Google Scholar 

  10. Maheswaran, S., Sequist, L. V., Nagrath, S., Ulkus, L., Brannigan, B., Collura, C. V., Inserra, E., Diederichs, S., Iafrate, A. J., Bell, D. W., Digumarthy, S., Muzikansky, A., Irimia, D., Settleman, J., Tompkins, R. G., Lynch, T. J., Toner, M., & Haber, D. A. (2008). Detection of mutations in EGFR in circulating lung-cancer cells. New England Journal of Medicine, 359, 366–377.

    Article  CAS  PubMed  Google Scholar 

  11. Krebs, M. G., Sloane, R., Priest, L., Lancashire, L., Hou, J. M., Greystoke, A., Ward, T. H., Ferraldeschi, R., Hughes, A., Clack, G., Ranson, M., Dive, C., & Blackhall, F. H. (2011). Evaluation and prognostic significance of circulating tumor cells in patients with non-small cell lung cancer. Journal of Clinical Oncology, 29, 1556–1563.

    Article  PubMed  Google Scholar 

  12. Morrison, R., Schleicher, S. M., Sun, Y., Niermann, K. J., Kim, S., & Spratt, D. E. (2011). Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. Journal of Oncology, 2011, 1–13. https://doi.org/10.1155/2011/941876.

    Article  CAS  Google Scholar 

  13. Dragu, D. L., Necula, L. G., Bleotu, C., Diaconu, C. C., & Chivu-Economescu, M. (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World Journal of Stem Cells., 7, 1185–1201.

    PubMed  PubMed Central  Google Scholar 

  14. Roudi, R., Madjd, Z., Korourian, A., Mehrazma, M., Molanae, S., Sabet, M. N., & Shariftabrizi, A. (2014). Clinical significance of putative cancer stem cell marker CD44 in different histological subtypes of lung cancer. Cancer Biomarkers, 14, 457–467.

    Article  CAS  PubMed  Google Scholar 

  15. Miranda-Lorenzo, I., Dorado, J., & Lonardo, E. (2014). Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods, 11, 1161–1169.

    Article  CAS  PubMed  Google Scholar 

  16. Detterbeck, F. C., Boffa, D. J., Kim, A. W., & Tanoue, L. T. (2017). The eight edition lung cancer classification. Chest Journal, 151, 193–203.

    Article  Google Scholar 

  17. Dziedzic, D., Peryt, A., Szolkowska, M., Langfort, R., & Orlowski, T. (2016). Evaluation of the diagnostic utility of endobronchial ultrasoundguided transbronchial needle aspiration for metastatic mediastinal tumors. Endoscopic Ultrasound, 5(3), 173–177.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Skirecki, T., Hoser, G., Kawiak, J., Dziedzic, D., & Domagała-Kulawik, J. (2014). Flow cytometric analysis of CD133- and EpCAM- positive cells in the peripheral blood of patients with lung cancer. Archivum Immunologiae et Therapiae Experimentalis, 62, 67–75.

    Article  CAS  PubMed  Google Scholar 

  19. Hou, J.-M. M., Krebs, M., & Ward, T. (2011). Circulating tumor cells as a window on metastasis biology in lung Cancer. Americal Journal of Pathology, 178, 989–996.

    Article  Google Scholar 

  20. Funaki, S., Sawabata, N., Abulaiti, A., Nakagiri, T., Shintani, Y., Inoue, M., Minami, M., & Okumura, M. (2013). Significance of tumour vessel invasion in determining the morphology of isolated tumour cells in the pulmonary vein in non-small-cell lung cancer. European Journal of Cardiothoracic Surgery, 43, 1126–1130.

    Article  PubMed  Google Scholar 

  21. Gwóźdź, P., Pasieka-Lis, M., & Kołodziej, K. (2018). Prognosis of patients with stages I and II non-small cell lung Cancer with nodal micrometastases. Annals of Thoracic Surgery, 105(5), 1551–1557.

    Article  PubMed  Google Scholar 

  22. Sakakibara, R., Inamura, K., Tambo, Y., Ninomiya, H., Kitazono, S., Yanagitani, N., Horiike, A., Ohyanagi, F., Matsuura, Y., Nakao, M., Mun, M., Okumura, S., Inase, N., Nishio, M., Motoi, N., & Ishikawa, Y. (2017). EBUS-TBNA as a promising method for the evaluation of tumor PD-L1 expression in lung Cancer. Clinical Lung Cancer, 18(5), 527–534.

    Article  CAS  PubMed  Google Scholar 

  23. Schatton, T., Schutte, U., Frank, N. Y., Zhan, Q., Hoerning, A., Robles, S. C., Zhou, J., Hodi, F. S., Spagnoli, G. C., Murphy, G. F., & Frank, M. H. (2010). Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Research, 70, 697–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, Y., & Sunwoo, J. (2014). PD-L1 is preferentially expressed on CD44+ tumor-initiating cells in head and neck squamous cell carcinoma. Journal for Immunotherapy of Cancer, 2, 270.

    Article  Google Scholar 

  25. Abetov, D., Mustapova, Z., Saliev, T., Bulanin, D., Batyrbekov, K., & Gilman, C. P. (2015). Novel small molecule inhibitors of Cancer stem cell signaling pathways. Stem Cell Reviews and Reports, 11, 909–918.

    Article  CAS  PubMed  Google Scholar 

  26. Liu, Y., Dong, Z., Jiang, T., Hou, L., Wu, F., Gao, G., He, Y., Zhao, J., Li, X., Zhao, C., Zhang, W., Tian, Q., Pan, Y., Wang, Y., Yang, S., Wu, C., Ren, S., Zhou, C., Zhang, J., & Hirsch, F. R. (2018). Heterogeneity of PD-L1 expression among the different histological components and metastatic lymph nodes in patients with resected lung Adenosquamous carcinoma. Clinical Lung Cancer, 19, e421–e430. https://doi.org/10.1016/j.cllc.2018.02.008.

    Article  CAS  PubMed  Google Scholar 

  27. Grigg, C., & Rizvi, N. A. (2016). PD-L1 biomarker testing for non-small cell lung cancer: truth or fiction? Journal for Immunotherapy of Cancer, 4, 48.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kim, S., Koh, J., Kim, M., et al. (2016). PD-L1 expression is associated with epithelial-to-mesenchymal transition in adenocarcinoma of the lung. Human Pathology, 58, 7–1.

    Article  CAS  PubMed  Google Scholar 

  29. Travis, W. D., Brambilla, E., Nicholson, A. G., Yatabe, Y., Austin, J. H. M., Beasley, M. B., Chirieac, L. R., Dacic, S., Duhig, E., Flieder, D. B., Geisinger, K., Hirsch, F. R., Ishikawa, Y., Kerr, K. M., Noguchi, M., Pelosi, G., Powell, C. A., Tsao, M. S., Wistuba, I., & WHO Panel. (2015). The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. Journal of Thoracic Oncology, 10, 1243–1260.

    Article  PubMed  Google Scholar 

  30. Langfort, R., & Szołkowska, M. (2012). Recommendation concerning the microscopic classification of lung adenocarcinoma presented by International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. Pneumonologia i Alergologia Polska, 80(2), 99–100.

    PubMed  Google Scholar 

  31. Dunn, G. P., Old, L. J., & Schreiber, R. D. (2004). The three Es of cancer immunoediting. Annual Review of Immunology, 22, 329–360.

    Article  CAS  PubMed  Google Scholar 

  32. Lou, Y., Diao, L., Parra Cuentas, E. R., et al. (2016). Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clinical Cancer Research, 22(14), 3630–3642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wu, T. F., Chen, L., Bu, L. L., Gao, J., Zhang, W. F., & Jia, J. (2017). CD44+ cancer cell-induced metastasis: a feasible neck metastasis model. European Journal of Pharmaceutical Sciences, 101, 243–250. https://doi.org/10.1016/j.ejps.2017.02.020.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang, L., Wang, D., Li, Y., Liu, Y., Xie, X., Wu, Y., Zhou, Y., Ren, J., Zhang, J., Zhu, H., & Su, Z. (2016). CCL21/CCR7 axis contributed to CD133(+) pancreatic cancer stem-like cell metastasis via EMT and Erk/NF-κB pathway. PLoS One, 11, e0158529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hashimoto, M., Tanaka, F., Yoneda, K., Takuwa, T., Matsumoto, S., Okumura, Y., Kondo, N., Tsubota, N., Tsujimura, T., Tabata, C., Nakano, T., & Hasegawa, S. (2014). Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. Interactive Cardiovascular and Thoracic Surgery, 18(6), 775–783.

    Article  PubMed  Google Scholar 

  36. Murlidhar, V., Reddy, R. M., Fouladdel, S., Zhao, L., Ishikawa, M. K., Grabauskiene, S., Zhang, Z., Lin, J., Chang, A. C., Carrott, P., Lynch, W. R., Orringer, M. B., Kumar-Sinha, C., Palanisamy, N., Beer, D. G., Wicha, M. S., Ramnath, N., Azizi, E., & Nagrath, S. (2017). Poor prognosis indicated by venous circulating tumor cell clusters in early stage lung cancers. Cancer Research, 77, 5194–5206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Marta Dabrowska MD, PhD, and Rafał Sokołowski MD for the help in EBUS/TBNA performing.

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Authors and Affiliations

  1. Department of Pathology, Medical University of Warsaw, Pawinskiego 7 Street, 02-106, Warsaw, Poland

    Agata Raniszewska

  2. Department of Internal Medicine and Hematology Laboratory of Flow Cytometry, u, Szaserow 128 Street, 04-141, Warsaw, Poland

    Agata Raniszewska & Elzbieta Rutkowska

  3. Department of Surgery, Institute of Tuberculosis and Lung Diseases, Plocka 26 Street, 01-138, Warsaw, Poland

    Małgorzata Polubiec-Kownacka

  4. Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Banacha 1a Street, 02-097, Warsaw, Poland

    Joanna Domagala-Kulawik

Authors
  1. Agata Raniszewska
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  2. Małgorzata Polubiec-Kownacka
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  3. Elzbieta Rutkowska
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  4. Joanna Domagala-Kulawik
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Correspondence to Joanna Domagala-Kulawik.

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Micro Abstract

• Lung cancer stem cells- CSCs could be responsible for escape from immunosurveillance.

• CSCs are identified by expression of CD133 and EpCAM.

• CD133+EpCAM+PD-L1+ cells are found in EBUS/TBNA samples of lymph nodes.

• Proportion of CSCs PD-L1+ is elevated in metastatic lymph nodes and in adenocarcinoma.

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Raniszewska, A., Polubiec-Kownacka, M., Rutkowska, E. et al. PD-L1 Expression on Lung Cancer Stem Cells in Metastatic Lymph Nodes Aspirates. Stem Cell Rev and Rep 15, 324–330 (2019). https://doi.org/10.1007/s12015-018-9860-7

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  • DOI: https://doi.org/10.1007/s12015-018-9860-7

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