Abstract
In lung cancer, the immune cell compartment of tumor-draining lymph nodes (TDLNs) dictate the response against tumors. This response is predominantly triggered by myeloid antigen-presenting cells (mAPCs) that capture antigens and, if matured, prime anti-tumor-specific T cell populations. However, the clinical role of mAPCs infiltrated in TDLN from lung cancer patients is poorly understood. The purpose of this study was to study mAPCs in TDLN from lung adenocarcinoma patients, in comparison to individuals with non-malignant diseases, using minimally invasive sampling methods. Mediastinal lymph nodes were assessed by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). mAPCs were characterized by flow cytometry and cytokine expression by quantitative polymerase chain reaction. The association with tumor burden, overall survival, and response to treatment was assessed. TDLN from lung adenocarcinoma patients (n = 24) showed a reduced immune cell compartment, but a higher level of infiltrating mAPCs, when compared with control lymph nodes (n = 17). A decreased expression of co-stimulatory molecules CD80/CD86 by TDLN and blood mAPC was observed. TDLN showed lower levels of TNF-α and IL-12 and increased levels of immunosuppressive cytokines TGF-β and IL-10. The IL-12 expression was inversely correlated with the percentage of infiltrated tumor cells, while IL-10 was directly correlated. Patients with lower expression of IL-12 in TDLN or lower expression of CD80/86 in blood mAPCs had worse overall survival and response to therapy. mAPCs of lung adenocarcinoma patients express less co-stimulatory molecules, and within TDLN, the cytokine profile is biased towards a tolerance-inducing phenotype. Patients with enhanced immune parameters have better survival and response to treatment. EBUS-TBNA allows the collection of viable specimens from TDLN that may provide further insight on relevant immunological mechanisms.
Similar content being viewed by others
References
Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.
Helissey C, Champiat S, Soria JC. Immune checkpoint inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015;27(2):108–17.
Mostafa AA, Morris DG. Immunotherapy for lung cancer: has it finally arrived? Front Oncol. 2014;4:288.
Langenkamp A, Messi M, Lanzavecchia A, Sallusto F. Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol. 2000;1(4):311–6.
Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.
Vicari AP, Caux C, Trinchieri G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol. 2002;12(1):33–42.
Carrascal MA, Severino PF, Guadalupe Cabral M, et al. Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells. Mol Oncol. 2014;8(3):753–65.
Fischer JR, Darjes H, Lahm H, Schindel M, Drings P, Krammer PH. Constitutive secretion of bioactive transforming growth factor beta 1 by small cell lung cancer cell lines. Eur J Cancer. 1994;30A(14):2125–9.
Huang M, Sharma S, Mao JT, Dubinett SM. Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production. J Immunol. 1996;157(12):5512–20.
Tabarkiewicz J, Rybojad P, Jablonka A, Rolinski J. CD1c+ and CD303+ dendritic cells in peripheral blood, lymph nodes and tumor tissue of patients with non-small cell lung cancer. Oncol Rep. 2008;19(1):237–43.
Schneider T, Hoffmann H, Dienemann H, et al. Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3. J Thorac Oncol. 2011;6(7):1162–8.
Bugalho A, Martins C, Dias SS, et al. Cytokeratin 19, carcinoembryonic antigen, and epithelial cell adhesion molecule detect lung cancer lymph node metastasis in endobronchial ultrasound-guided transbronchial aspiration samples. Clin Lung Cancer. 2013;14(6):704–12.
Bugalho A, Doris MK, Hamacher J, Eberhardt R, Herth FJ. Endobronchial ultrasound: practical aspects and clinical applications. Rev Port Pneumol. 2008;14(1):55–88.
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest. 2009;136(1):260–71.
Videira PA, Correia M, Malagolini N, et al. ST3Gal.I sialyltransferase relevance in bladder cancer tissues and cell lines. BMC Cancer. 2009;9(Journal Article):357.
Silva Z, Tong Z, Cabral MG, et al. Sialyl Lewisx-dependent binding of human monocyte-derived dendritic cells to selectins. Biochem Biophys Res Commun. 2011;409(3):459–64.
Videira PA, Amado IF, Crespo HJ, et al. Surface alpha 2-3- and alpha 2-6-sialylation of human monocytes and derived dendritic cells and its influence on endocytosis. Glycoconj J. 2008;25(3):259–68.
Bugalho A, Ferreira D, Eberhardt R, et al. Diagnostic value of endobronchial and endoscopic ultrasound-guided fine needle aspiration for accessible lung cancer lesions after non-diagnostic conventional techniques: a prospective study. BMC Cancer. 2013;13:130.
Zieliński P, Dyszkiewicz W, Piwkowski CT, Dworacki G, Gasiorowski L. Can the condition of the cell microenvironment of mediastinal lymph nodes help predict the risk of metastases in non-small cell lung cancer? Cancer Epidemiol. 2009;33(5):387–90.
Pyfferoen L, Mestdagh P, Vergote K, et al. Lung tumours reprogram pulmonary dendritic cell immunogenicity at the microRNA level. Int J Cancer. 2014;135(12):2868–77.
Orentas RJ, Kohler ME, Johnson BD. Suppression of anti-cancer immunity by regulatory T cells: back to the future. Semin Cancer Biol. 2006;16(2):137–49.
Hegde S, Pahne J, Smola-Hess S. Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-kappaB binding activity and CCR7 expression. FASEB J. 2004;18(12):1439–41.
Culig Z. Cytokine disbalance in common human cancers. Biochim Biophys Acta. 2011;1813(2):308–14.
Songür N, Kuru B, Kalkan F, Ozdilekcan C, Cakmak H, Hizel N. Serum interleukin-6 levels correlate with malnutrition and survival in patients with advanced non-small cell lung cancer. Tumori. 2004;90(2):196–200.
Gomes M, Coelho A, Araújo A, et al. IL-6 polymorphism in non-small cell lung cancer: a prognostic value? Tumour Biol. 2015;36(5):3679–84.
Han RX, Liu X, Pan P, Jia YJ, Yu JC. Effectiveness and safety of chemotherapy combined with dendritic cells co-cultured with cytokine-induced killer cells in the treatment of advanced non-small-cell lung cancer: a systematic review and meta-analysis. PLoS One. 2014;9(9):e108958.
Holt GE, Podack ER, Raez LE. Immunotherapy as a strategy for the treatment of non-small-cell lung cancer. Therapy. 2011;8(1):43–54.
Carbone DP, Gandara DR, Antonia SJ, Zielinski C, Paz-Ares L. Non-small-cell lung cancer: role of the immune system and potential for immunotherapy. J Thorac Oncol. 2015;10(7):974–84.
Acknowledgments
We thank Manuela Correia for the technical assistance.
Conflicts of interest
None
Funding sources
None
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bugalho, A., Martins, C., Silva, Z. et al. Immature myeloid cells and tolerogenic cytokine profile in lung adenocarcinoma metastatic lymph nodes assessed by endobronchial ultrasound. Tumor Biol. 37, 953–961 (2016). https://doi.org/10.1007/s13277-015-3885-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13277-015-3885-1