Skip to main content
SpringerLink
Log in

The cytokine milieu compromises functional capacity of tumor-infiltrating plasmacytoid dendritic cells in HPV-negative but not in HPV-positive HNSCC

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability and material

Data are available on a reasonable request from the corresponding authors.

References

  1. Mork J, Lie AK, Glattre E, Hallmans G, Jellum E, Koskela P, Moller B, Pukkala E, Schiller JT, Youngman L, Lehtinen M, Dillner J (2001) Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344(15):1125–1131. https://doi.org/10.1056/NEJM200104123441503

    Article  CAS  PubMed  Google Scholar 

  2. Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14(2):467–475. https://doi.org/10.1158/1055-9965.EPI-04-0551

    Article  CAS  PubMed  Google Scholar 

  3. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35. https://doi.org/10.1056/NEJMoa0912217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269. https://doi.org/10.1093/jnci/djn011

    Article  CAS  PubMed  Google Scholar 

  5. El-Naggar AK, Westra WH (2012) p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck 34(4):459–461. https://doi.org/10.1002/hed.21974

    Article  PubMed  Google Scholar 

  6. Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP (2017) Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 67 (2):122–137. doi:https://doi.org/10.3322/caac.21389

  7. Network NCC NCCN Clinical Practice Guidelines in Oncology, Head and Neck Cancers ( Version 1/2018). https://www.nccn.org/.

  8. Deschuymer S, Mehanna H, Nuyts S (2018) Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches. Front Oncol 8:439. https://doi.org/10.3389/fonc.2018.00439

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375(19):1856–1867. https://doi.org/10.1056/NEJMoa1602252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mehra R, Seiwert TY, Gupta S, Weiss J, Gluck I, Eder JP, Burtness B, Tahara M, Keam B, Kang H, Muro K, Geva R, Chung HC, Lin CC, Aurora-Garg D, Ray A, Pathiraja K, Cheng J, Chow LQM, Haddad R (2018) Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119(2):153–159. https://doi.org/10.1038/s41416-018-0131-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Partlova S, Boucek J, Kloudova K, Lukesova E, Zabrodsky M, Grega M, Fucikova J, Truxova I, Tachezy R, Spisek R, Fialova A (2015) Distinct patterns of intratumoral immune cell infiltrates in patients with HPV-associated compared to non-virally induced head and neck squamous cell carcinoma. Oncoimmunology 4(1):e965570. https://doi.org/10.4161/21624011.2014.965570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, Lee KW, Ganly I, Hakimi AA, Chan TA, Morris LG (2016) The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1(17):e89829. https://doi.org/10.1172/jci.insight.89829

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hladikova K, Koucky V, Boucek J, Laco J, Grega M, Hodek M, Zabrodsky M, Vosmik M, Rozkosova K, Vosmikova H, Celakovsky P, Chrobok V, Ryska A, Spisek R, Fialova A (2019) Tumor-infiltrating B cells affect the progression of oropharyngeal squamous cell carcinoma via cell-to-cell interactions with CD8(+) T cells. J Immunother Cancer 7(1):261. https://doi.org/10.1186/s40425-019-0726-6

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T, Okada T, Vermi W, Winkels G, Yamamoto T, Zysk M, Yamaguchi Y, Schmitz J (2001) BDCA-2, a novel plasmacytoid dendritic cell-specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 194(12):1823–1834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, Buck DW, Schmitz J (2000) BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165(11):6037–6046

    Article  CAS  PubMed  Google Scholar 

  16. Tel J, Smits EL, Anguille S, Joshi RN, Figdor CG, de Vries IJ (2012) Human plasmacytoid dendritic cells are equipped with antigen-presenting and tumoricidal capacities. Blood 120(19):3936–3944. https://doi.org/10.1182/blood-2012-06-435941

    Article  CAS  PubMed  Google Scholar 

  17. Martin-Gayo E, Sierra-Filardi E, Corbi AL, Toribio ML (2010) Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood 115(26):5366–5375. https://doi.org/10.1182/blood-2009-10-248260

    Article  CAS  PubMed  Google Scholar 

  18. Chaperot L, Blum A, Manches O, Lui G, Angel J, Molens JP, Plumas J (2006) Virus or TLR agonists induce TRAIL-mediated cytotoxic activity of plasmacytoid dendritic cells. J Immunol 176(1):248–255

    Article  CAS  PubMed  Google Scholar 

  19. Liu C, Lou Y, Lizee 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(3):1165–1175. https://doi.org/10.1172/JCI33583

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Koucky V, Boucek J, Fialova A (2019) Immunology of plasmacytoid dendritic cells in solid tumors: a brief review. Cancers. https://doi.org/10.3390/cancers11040470

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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(22):7466–7474. https://doi.org/10.1158/1078-0432.CCR-04-0684

    Article  CAS  PubMed  Google Scholar 

  22. 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(3):380–382. https://doi.org/10.4161/onci.18801

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jensen TO, Schmidt H, Moller HJ, Donskov F, Hoyer 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(9):2476–2485. https://doi.org/10.1002/cncr.26511

    Article  CAS  PubMed  Google Scholar 

  24. Hartmann E, Wollenberg B, Rothenfusser S, Wagner M, Wellisch D, Mack B, Giese T, Gires O, Endres S, Hartmann G (2003) Identification and functional analysis of tumor-infiltrating plasmacytoid dendritic cells in head and neck cancer. Cancer Res 63(19):6478–6487

    CAS  PubMed  Google Scholar 

  25. Han N, Zhang Z, Liu S, Ow A, Ruan M, Yang W, Zhang C (2017) Increased tumor-infiltrating plasmacytoid dendritic cells predicts poor prognosis in oral squamous cell carcinoma. Arch Oral Biol 78:129–134. https://doi.org/10.1016/j.archoralbio.2017.02.012

    Article  CAS  PubMed  Google Scholar 

  26. Yang LL, Mao L, Wu H, Chen L, Deng WW, Xiao Y, Li H, Zhang L, Sun ZJ (2019) pDC depletion induced by CD317 blockade drives the antitumor immune response in head and neck squamous cell carcinoma. Oral Oncol 96:131–139. https://doi.org/10.1016/j.oraloncology.2019.07.019

    Article  CAS  PubMed  Google Scholar 

  27. Sisirak V, Faget J, Vey N, Blay JY, Menetrier-Caux C, Caux C, Bendriss-Vermare N (2013) Plasmacytoid dendritic cells deficient in IFNalpha production promote the amplification of FOXP3(+) regulatory T cells and are associated with poor prognosis in breast cancer patients. Oncoimmunology 2(1):e22338. https://doi.org/10.4161/onci.22338

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sisirak V, Vey N, Goutagny N, Renaudineau S, Malfroy M, Thys S, Treilleux I, Labidi-Galy SI, Bachelot T, Dezutter-Dambuyant C, Menetrier-Caux C, Blay JY, Caux C, Bendriss-Vermare N (2013) Breast cancer-derived transforming growth factor-beta and tumor necrosis factor-alpha compromise interferon-alpha production by tumor-associated plasmacytoid dendritic cells. Int J Cancer 133(3):771–778. https://doi.org/10.1002/ijc.28072

    Article  CAS  PubMed  Google Scholar 

  29. Fuchs A, Cella M, Kondo T, Colonna M (2005) Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44. Blood 106(6):2076–2082. https://doi.org/10.1182/blood-2004-12-4802

    Article  CAS  PubMed  Google Scholar 

  30. Labidi-Galy SI, Sisirak V, Meeus P, Gobert M, Treilleux I, Bajard A, Combes JD, Faget J, Mithieux F, Cassignol A, Tredan O, Durand I, Menetrier-Caux C, Caux C, Blay JY, Ray-Coquard I, Bendriss-Vermare N (2011) Quantitative and functional alterations of plasmacytoid dendritic cells contribute to immune tolerance in ovarian cancer. Cancer Res 71(16):5423–5434. https://doi.org/10.1158/0008-5472.CAN-11-0367

    Article  CAS  PubMed  Google Scholar 

  31. Bruchhage KL, Heinrichs S, Wollenberg B, Pries R (2018) IL-10 in the microenvironment of HNSCC inhibits the CpG ODN induced IFN-alpha secretion of pDCs. Oncol Lett 15(3):3985–3990. https://doi.org/10.3892/ol.2018.7772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Demoulin S, Herfs M, Somja J, Roncarati P, Delvenne P, Hubert P (2015) HMGB1 secretion during cervical carcinogenesis promotes the acquisition of a tolerogenic functionality by plasmacytoid dendritic cells. Int J Cancer 137(2):345–358. https://doi.org/10.1002/ijc.29389

    Article  CAS  PubMed  Google Scholar 

  33. Duramad O, Fearon KL, Chan JH, Kanzler H, Marshall JD, Coffman RL, Barrat FJ (2003) IL-10 regulates plasmacytoid dendritic cell response to CpG-containing immunostimulatory sequences. Blood 102(13):4487–4492. https://doi.org/10.1182/blood-2003-07-2465

    Article  CAS  PubMed  Google Scholar 

  34. Popovic PJ, DeMarco R, Lotze MT, Winikoff SE, Bartlett DL, Krieg AM, Guo ZS, Brown CK, Tracey KJ, Zeh HJ 3rd (2006) High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists. J Immunol 177(12):8701–8707. https://doi.org/10.4049/jimmunol.177.12.8701

    Article  CAS  PubMed  Google Scholar 

  35. Parks RR, Yan SD, Huang CC (1994) Tumor necrosis factor-alpha production in human head and neck squamous cell carcinoma. Laryngoscope 104(7):860–864. https://doi.org/10.1288/00005537-199407000-00015

    Article  CAS  PubMed  Google Scholar 

  36. Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S (1999) Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res 90(8):858–866. https://doi.org/10.1111/j.1349-7006.1999.tb00827.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ito T, Yang M, Wang YH, Lande R, Gregorio J, Perng OA, Qin XF, Liu YJ, Gilliet M (2007) Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand. J Exp Med 204(1):105–115. https://doi.org/10.1084/jem.20061660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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(20):5188–5197. https://doi.org/10.1158/0008-5472.CAN-11-3468

    Article  CAS  PubMed  Google Scholar 

  39. Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, Bukkapatnam S, Van Court B, Uyanga N, Darragh L, Kim HM, Raben D, Tan AC, Heasley L, Clambey E, Nemenoff R, Karam SD (2018) Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-Cell infiltration. Clin Cancer Res 24(21):5368–5380. https://doi.org/10.1158/1078-0432.CCR-18-1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The major sponsor of this study was Sotio a.s. The project was partly supported by the Grant Agency of Charles University in Prague, project No. 668217. We thank the nursing and medical staff at the Department of Otorhinolaryngology and Head and Neck Surgery, First Medical Faculty, Motol University Hospital, for their indispensable cooperation in the study.

Funding

The major sponsor of this study was Sotio a.s. The project was partly supported by the Grant Agency of Charles University in Prague, project No. 668217.

Author information

Authors and Affiliations

  1. Sotio, Prague, Czech Republic

    Vladimír Koucký, Kamila Hladíková, Eliška Táborská, Radek Špíšek & Anna Fialová

  2. Department of Otorhinolaryngology and Head and Neck Surgery, First Medical Faculty, Motol University Hospital, Prague, Czech Republic

    Vladimír Koucký & Jan Bouček

  3. Department of Pathology and Molecular Medicine, Second Medical Faculty, Motol University Hospital, Prague, Czech Republic

    Marek Grega

Authors
  1. Vladimír Koucký
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kamila Hladíková
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eliška Táborská
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan Bouček
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marek Grega
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Radek Špíšek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anna Fialová
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VK designed and performed the experiments, collected native tumor tissue and blood samples, collected and evaluated clinical data and wrote the article; KH and ET performed the experiments and provided critical reading of the manuscript; JB coordinated collection of the native tumor tissue samples and clinical data and provided critical reading of the manuscript; MG prepared paraffin-embedded sections and native tumor tissue samples and provided pathologic staging of the patients; RS supervised design of the study and performed critical reading of the manuscript; AF designed the study, supervised experiments, performed data analysis and wrote the article.

Corresponding authors

Correspondence to Vladimír Koucký or Anna Fialová.

Ethics declarations

Conflict of interest

Vladimír Koucký, Kamila Hladíková, Eliška Táborská, Radek Špíšek and Anna Fialová are employees of Sotio, a biotechnological company, which develops new therapies focusing on the treatment of cancer and autoimmune diseases. Authors declare no competing financial interests.

Consent to participate

All patients and healthy donors enrolled in this study signed an informed consent, which was approved by the Ethics Committee of the Motol University Hospital, Prague, Czech Republic.

Ethics approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Declaration of Helsinki and its later amendments. The study was approved by the Ethics Committee of the Motol University Hospital, Prague, Czech Republic (No. 1320/16).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koucký, V., Hladíková, K., Táborská, E. et al. The cytokine milieu compromises functional capacity of tumor-infiltrating plasmacytoid dendritic cells in HPV-negative but not in HPV-positive HNSCC. Cancer Immunol Immunother 70, 2545–2557 (2021). https://doi.org/10.1007/s00262-021-02874-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-02874-y

Keywords

Search

Navigation