Abstract
Background and aim
Lung cancer is the number one cause of cancer-related deaths. Dendritic cells (DCs) are heterogeneous components of innate immunity that play a crucial role in the anti-tumor T cell immunity and may represent a promising approach for tumor immunotherapy. In this study, we aimed to evaluate the frequency of the two major subsets of DCs; plasmacytoid dendritic cells (pDCs) and monocytic dendritic cells (mDCs) in non-small cell lung cancer (NCSLC) and correlating them with different clinicopathologic features and survival outcomes.
Patients and methods
This study was a case-controlled one, included 50 patients with denovo pathologically confirmed NSCLC and 20 healthy controls of comparable age and gender. After diagnosis and staging of patients, the frequency of DCs was evaluated using flow cytometry.
Results
We unveiled significantly reduced levels of pDCs (P = 0.024), and mDCs (P = 0.013) in NSCLC patients compared to controls. Furthermore, there was a significant accumulation of pDCs in non-metastatic patients compared to metastatic ones (P < 0.0001), while there was no significant (P = 0.6) differences in mDCs, and mDCs/pDCs ratio (P = 0.9). There was a Significant negative correlation (r = − 0.3, P = 0.04) between OS and mDCs. On the other hand, there was a significantly higher OS with pDCs ≥ 0.82 compared to patients with pDCs < 0.82, log rank Ch2 = 12.128, P < 0.0001.
Conclusion
Despite the controversy about the prognostic role of pDCs not only in NSCLC but also in other solid tumors, our study sheds light on the possible prognostic impact of pDCs and mDCs on treatment outcomes of NSCLC patients.
Similar content being viewed by others
Data availability
Data are available whenever requested
References
Zhang Z, Jiang J, Wu X, Zhang M, Luo D, Zhang R, Li S, He Y, Bian H, Chen Z (2019) Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy. Front Med 13:57–68
Hetta HF, Zahran AM, Shafik EA, El-Mahdy RI, Mohamed NA, Nabil EE, Esmaeel HM, Alkady OA, Elkady A, Mohareb DA (2019) Circulating miRNA-21 and miRNA-23a expression signature as potential biomarkers for early detection of non-small-cell lung cancer. Microrna 8:206–215
Hetta HF, Zahran AM, El-Mahdy RI, Nabil EE, Esmaeel HM, Alkady OA, Elkady A, Mohareb DA, Mostafa MM, John J (2019) Assessment of circulating miRNA-17 and miRNA-222 expression profiles as non-invasive biomarkers in Egyptian patients with non-small-cell lung cancer. Asian Pac J Cancer Prev 20:1927
Pandey D, Ramanathan P, Pandey R, Mediastinal PK (2017) staging for non-small cell lung cancer revisited. It is being done under aegis of ICON and Lung cancer consortium asia. Indian J Cancer 54(1):68–72
Hersom M, Jorgensen JT (2018) Companion and complementary diagnostics-focus on PD-L1 expression assays for PD-1/PD-L1 checkpoint inhibitors in non-small cell lung cancer. Ther Drug Monit 40:9–16
Ancevski Hunter K, Socinski MA, Villaruz LC (2018) PD-L1 testing in guiding patient selection for PD-1/PD-L1 inhibitor therapy in lung cancer. Mol Diagn Ther 22:1–10
Chae YK, Arya A, Iams W, Cruz MR, Chandra S, Choi J, Giles F (2018) Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer 6:39
Murphy TL, Grajales-Reyes GE, Wu X, Tussiwand R, Briseno CG, Iwata A, Kretzer NM, Durai V, Murphy KM (2016) Transcriptional control of dendritic cell development. Annu Rev Immunol 34:93–119
Villadangos JA, Young L (2008) Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29:352–361
Matta BM, Castellaneta A, Thomson AW (2010) Tolerogenic plasmacytoid DC. Eur J Immunol 40:2667–2676
Young LJ, Wilson NS, Schnorrer P, Proietto A, ten Broeke T, Matsuki Y, Mount AM, Belz GT, O'Keeffe M, Ohmura-Hoshino M, Ishido S, Stoorvogel W, Heath WR, Shortman K, Villadangos JA (2008) Differential MHC class II synthesis and ubiquitination confers distinct antigen-presenting properties on conventional and plasmacytoid dendritic cells. Nat Immunol 9:1244–1252
Aspord C, Leccia MT, Charles J, Plumas J (2013) Plasmacytoid dendritic cells support melanoma progression by promoting Th2 and regulatory immunity through OX40L and ICOSL. Cancer Immunol Res 1:402–415
Sisirak V, Faget J, Gobert M, Goutagny N, Vey N, Treilleux I, Renaudineau S, Poyet G, Labidi-Galy SI, Goddard-Leon S, Durand I, Le Mercier I, Bajard A, Bachelot T, Puisieux A, Puisieux I, Blay JY, Menetrier-Caux C, Caux C, Bendriss-Vermare N (2012) Impaired IFN-alpha production by plasmacytoid dendritic cells favors regulatory T-cell expansion that may contribute to breast cancer progression. Cancer Res 72:5188–5197
Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, Chen JL, Keller AM, Joffre O, Zelenay S, Nye E, Le Moine A, Faure F, Donckier V, Sancho D, Cerundolo V, Bonnet D, Reis E, Sousa C (2010) Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med 207(6):1261–1271
Segura E, Amigorena S (2015) Cross-presentation in mouse and human dendritic cells. Adv Immunol 127:1–31
Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM (2019) Human Dendritic Cells: Their Heterogeneity and Clinical Application Potential in Cancer Immunotherapy. Front Immunol. https://doi.org/10.3389/fimmu.2018.03176
Sanchez-Paulete AR, Cueto FJ, Martinez-Lopez M, Labiano S, Morales-Kastresana A, Rodriguez-Ruiz ME, Jure-Kunkel M, Azpilikueta A, Aznar MA, Quetglas JI, Sancho D, Melero I (2016) Cancer immunotherapy with immunomodulatory Anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov 6:71–79
Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, Casanova-Acebes M, Khudoynazarova M, Agudo J, Tung N, Chakarov S, Rivera C, Hogstad B, Bosenberg M, Hashimoto D, Gnjatic S, Bhardwaj N, Palucka AK, Brown BD, Brody J, Ginhoux F, Merad M (2016) Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44:924–938
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424
Larsen TV, Hussmann D, Nielsen AL (2019) PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer. Cancer Commun (Lond) 39:30
Wojas-Krawczyk K, Kalinka E, Grenda A, Krawczyk P, Milanowski J (2019) Beyond PD-L1 markers for lung cancer immunotherapy. Int J Mol Sci 20:1915
Qin A, Coffey DG, Warren EH, Ramnath N (2016) Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 5:2567–2578
Medrano RFV, Hunger A, Mendonça SA, Barbuto JAM, Strauss BE (2017) Immunomodulatory and antitumor effects of type I interferons and their application in cancer therapy. Oncotarget 8(41):71249–71284
Sorrentino R, Morello S, Forte G, Montinaro A, Vita GD, Luciano A, Palma G, Arra C, Maiolino P, Adcock IM, Pinto A (2011) B Cells contribute to the antitumor activity of CpG-oligodeoxynucleotide in a mouse model of metastatic lung carcinoma. Am J Respir Crit Care Med 183:1369–1379
Shi W, Li X, Porter JL, Ostrodi DH, Yang B, Li J, Wang Y, Zhang J, Bai L, Jiao S (2014) Level of plasmacytoid dendritic cells is increased in non-small cell lung carcinoma. Tumor Biol 35:2247–2252
Wang J-B, Huang X, Li F-R (2019) Impaired dendritic cell functions in lung cancer: a review of recent advances and future perspectives. Cancer Commun 39:43
Kini Bailur J, Gueckel B, Pawelec G (2016) Prognostic impact of high levels of circulating plasmacytoid dendritic cells in breast cancer. J Transl Med 14:151–151
Treilleux I, Blay JY, Bendriss-Vermare N, Ray-Coquard I, Bachelot T, Guastalla JP, Bremond A, Goddard S, Pin JJ, Barthelemy-Dubois C, Lebecque S (2004) Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res 10:7466–7474
Monti M, Consoli F, Vescovi R, Bugatti M, Vermi W (2020) Human plasmacytoid dendritic cells and cutaneous melanoma. Cells 9(2):417. https://doi.org/10.3390/cells9020417
Liu C, Lou Y, Lizée G, Qin H, Liu S, Rabinovich B, Kim GJ, Wang YH, Ye Y, Sikora AG, Overwijk WW, Liu YJ, Wang G, Hwu P (2008) Plasmacytoid dendritic cells induce NK cell-dependent, tumor antigen-specific T cell cross-priming and tumor regression in mice. J Clin Invest 118:1165–1175
Chevolet I, Speeckaert R, Schreuer M, Neyns B, Krysko O, Bachert C, Van Gele M, van Geel N, Brochez L (2015) Clinical significance of plasmacytoid dendritic cells and myeloid-derived suppressor cells in melanoma. J Transl Med 13:9
Jensen TO, Schmidt H, Møller HJ, Donskov F, Høyer M, Sjoegren P, Christensen IJ, Steiniche T (2012) Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118:2476–2485
Liu X, Yu H, Yan C, Mei Y, Lin C, Hong Y, Lin X, Zhang Q, Yu J (2019) Plasmacytoid dendritic cells and ICOS(+) regulatory t cells predict poor prognosis in gastric cancer: a pilot study. J Cancer 10:6711–6715
Huang XM, Liu XS, Lin XK, Yu H, Sun JY, Liu XK, Chen C, Jin HL, Zhang GE, Shi XX, Zhang Q, Yu JR (2014) Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer. Cancer Sci 105:150–158
Labidi-Galy SI, Treilleux I, Goddard-Leon S, Combes JD, Blay JY, Ray-Coquard I, Caux C, Bendriss-Vermare N (2012) Plasmacytoid dendritic cells infiltrating ovarian cancer are associated with poor prognosis. Oncoimmunology 1:380–382
Candolfi M, King GD, Yagiz K, Curtin JF, Mineharu Y, Muhammad AK, Foulad D, Kroeger KM, Barnett N, Josien R, Lowenstein PR, Castro MG (2012) Plasmacytoid dendritic cells in the tumor microenvironment: immune targets for glioma therapeutics. Neoplasia 14:757–770
Tjomsland V, Sandström P, Spångeus A, Messmer D, Emilsson J, Falkmer U, Falkmer S, Magnusson K-E, Borch K, Larsson M (2010) Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity? BMC Cancer 10:87–87
Chaux P, Moutet M, Faivre J, Martin F, Martin M (1996) Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7–1 and B7–2 costimulatory molecules of the T-cell activation. Lab Invest 74:975–983
Tourkova IL, Shurin GV, Wei S, Shurin MR (2007) Small rho GTPases mediate tumor-induced inhibition of endocytic activity of dendritic cells. J Immunol 178:7787–7793
Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, Kroemer G, Martin F, Chauffert B, Zitvogel L (2005) Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med 202:919–929
Hirsh V (2011) Review of the treatment of metastatic non small cell lung carcinoma: a practical approach. World J Clin Oncol 2:262–271
Choi MK, Hong JY, Chang W, Kim M, Kim S, Jung HA, Lee SJ, Park S, Chung MP, Sun JM, Park K, Ahn MJ, Ahn JS (2014) Safety and efficacy of gemcitabine or pemetrexed in combination with a platinum in patients with non-small-cell lung cancer and prior interstitial lung disease. Cancer Chemother Pharmacol 73:1217–1225
Aktipis CA, Nesse RM (2013) Evolutionary foundations for cancer biology. Evol Appl 6:144–159
Kelly RJ, Gulley JL, Giaccone G (2010) Targeting the immune system in non-small-cell lung cancer: bridging the gap between promising concept and therapeutic reality. Clin Lung Cancer 11:228–237
Maggi E (2010) T-cell responses induced by allergen-specific immunotherapy. Clin Exp Immunol 161:10–18
Yang L, Ren B, Li H, Yu J, Cao S, Hao X, Ren X (2013) Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients. Cancer Immunol Immunother 62:65–73
Thomas AA, Ernstoff MS, Fadul CE (2012) Immunotherapy for the treatment of glioblastoma. Cancer J 18:59–68
Zhang L, Yang X, Sun Z, Li J, Zhu H, Li J, Pang Y (2016) Dendritic cell vaccine and cytokine-induced killer cell therapy for the treatment of advanced non-small cell lung cancer. Oncol Lett 11:2605–2610
Funding
The authors declare that they did not receive any grant from their university or other funding agency
Author information
Authors and Affiliations
Contributions
AMZ, HFH, AR and ESS conceived and designed the experiments. AR, ESS and recruited patients, carried out the clinical investigations and collected patient’s clinical data. AMZ, HFH and SM performed the experiments. AMZ, HFH and SM shared in the analysis of the flow cytometry data. AR performed the statistical analysis. AR and AMZ accomplished the interpretation of results and wrote the initial draft. All authors participated in critical review and revision of the final manuscript. HFH is the corresponding author and managed the submission of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they had no conflict of interest
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zahran, A.M., Hetta, H.F., Mansour, S. et al. Reviving up dendritic cells can run cancer immune wheel in non-small cell lung cancer: a prospective two-arm study. Cancer Immunol Immunother 70, 733–742 (2021). https://doi.org/10.1007/s00262-020-02704-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-020-02704-7