HNO

, Volume 66, Issue 4, pp 296–300 | Cite as

B-Zellen in der Kopf-Hals-Onkologie

Leitthema

Zusammenfassung

Da die Immuntherapie bei der Behandlung des Kopf-Hals-Karzinoms einen immer größeren Stellenwert einnimmt, ist ein grundlegendes Verständnis der immunologischen Zusammenhänge im Tumormikromilieu wichtig. Hierbei ist die Bedeutung der tumorinfiltrierenden B‑Zellen (TIL-B) bisher weitgehend vernachlässigt worden. In der aktuellen Literatur wird allerdings ein wesentlicher Einfluss der B‑Zellen auf das Tumorwachstum beschrieben, sodass diese Zellgruppe nun auch als therapeutische Zielstruktur wahrgenommen wird. Regulatorische B‑Zellen (Breg) stellen eine Subgruppe der B‑Zellen mit immunsuppressiven Eigenschaften dar. Neben der Sekretion von Interleukin(IL)-10 werden Breg u. a. durch die Fähigkeit zur Adenosinproduktion definiert. Adenosin ist als immunsuppressiver Botenstoff im Tumormikromilieu bekannt, dessen Wirkung durch immuntherapeutische Ansätze unterbunden werden kann. Das Verständnis der tumorimmunologischen Zusammenhänge inklusive der verschiedenen B‑Zell-Funktionen kann helfen, die verschiedenen therapeutischen Ansätze, wie Chirurgie und Radiochemotherapie, mit der Immuntherapie effektiver zu kombinieren. Im vorliegenden Artikel werden die bisherigen Erkenntnisse über B‑Zellen und Adenosin im Kopf-Hals-Karzinom dargestellt.

Schlüsselwörter

B-Lymphozyten B-Lymphozyten-Untergruppen Regulatorische B‑Zellen Adenosin Kopf-Hals-Tumoren 

B cells in head and neck oncology

Abstract

As immunotherapy is becoming increasingly important in the treatment of head and neck cancer, a fundamental understanding of the immunological relationships in the tumor microenvironment is required. The importance of tumor-infiltrating B cells (TIL-B) has been largely neglected so far. In the current literature, however, a significant influence of B cells on tumor growth is described, so that this cell population is now also perceived as a therapeutic target structure. Regulatory B cells (Breg) represent a subset of B cells with immunosuppressive properties. In addition to the secretion of IL-10, Breg can be defined by their ability to produce adenosine. Adenosine is known as an immunosuppressive messenger in the tumor microenvironment whose effect can be prevented by immunotherapeutic approaches. Understanding the tumor immunological relationships, including the different B‑cell functions, can help to effectively combine standard approaches including surgery or radiochemotherapy with immunotherapy. In the present article, recent findings on B cells and adenosine in head and neck cancer are described.

Keywords

B-lymphocytes B-lymphocyte subsets Regulatory B cells Adenosine Head and neck neoplasms 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

P.J. Schuler, C. Brunner und T.K. Hoffmann geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Affara NI, Ruffell B, Medler TR et al (2014) B cells regulate macrophage phenotype and response to chemotherapy in squamous carcinomas. Cancer Cell 25:809–821CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ammirante M, Luo JL, Grivennikov S et al (2010) B‑cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464:302–305CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Barbera-Guillem E, Nelson MB, Barr B et al (2000) B lymphocyte pathology in human colorectal cancer. Experimental and clinical therapeutic effects of partial B cell depletion. Cancer Immunol Immunother 48:541–549CrossRefPubMedGoogle Scholar
  4. 4.
    Beavis PA, Milenkovski N, Henderson MA et al (2015) Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T‑cell responses. Cancer Immunol Res 3:506–517CrossRefPubMedGoogle Scholar
  5. 5.
    Beckenkamp A, Santana DB, Bruno AN et al (2014) Ectonucleotidase expression profile and activity in human cervical cancer cell lines. Biochem Cell Biol 92:95–104CrossRefPubMedGoogle Scholar
  6. 6.
    Chen JF, Eltzschig HK, Fredholm BB (2013) Adenosine receptors as drug targets—what are the challenges? Nat Rev Drug Discov 12:265–286CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dong HP, Elstrand MB, Holth A et al (2006) NK- and B‑cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am J Clin Pathol 125:451–458CrossRefPubMedGoogle Scholar
  8. 8.
    Eini H, Frishman V, Yulzari R et al (2015) Caffeine promotes anti-tumor immune response during tumor initiation: involvement of the adenosine A2A receptor. Biochem Pharmacol 98:110–118CrossRefPubMedGoogle Scholar
  9. 9.
    Ferris RL, Blumenschein G Jr., Fayette J et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Figueiro F, Muller L, Funk S et al (2016) Phenotypic and functional characteristics of CD39(high) human regulatory B cells (Breg). Oncoimmunology 5:e1082703CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Flynn NJ, Somasundaram R, Arnold KM et al (2017) The multifaceted roles of B cells in solid tumors: emerging treatment opportunities. Target Oncol 12:139–152CrossRefPubMedGoogle Scholar
  12. 12.
    Germain C, Gnjatic S, Tamzalit F et al (2014) Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. Am J Respir Crit Care Med 189:832–844CrossRefPubMedGoogle Scholar
  13. 13.
    Guan H, Lan Y, Wan Y et al (2016) PD-L1 mediated the differentiation of tumor-infiltrating CD19(+) B lymphocytes and T cells in invasive breast cancer. Oncoimmunology 5:e1075112CrossRefPubMedGoogle Scholar
  14. 14.
    Jie HB, Schuler PJ, Lee SC et al (2015) CTLA-4(+) regulatory T cells increased in cetuximab-treated head and neck cancer patients suppress NK cell cytotoxicity and correlate with poor prognosis. Cancer Res 75:2200–2210CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kasama H, Sakamoto Y, Kasamatsu A et al (2015) Adenosine A2b receptor promotes progression of human oral cancer. BMC Cancer 15:563CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kemp TJ, Moore JM, Griffith TS (2004) Human B cells express functional TRAIL/Apo-2 ligand after CpG-containing oligodeoxynucleotide stimulation. J Immunol 173:892–899CrossRefPubMedGoogle Scholar
  17. 17.
    Kim DG, Bynoe MS (2016) A2A adenosine receptor modulates drug efflux transporter P‑glycoprotein at the blood-brain barrier. J Clin Invest 126:1717–1733CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kroeger DR, Milne K, Nelson BH (2016) Tumor infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T cell responses, and superior prognosis in ovarian cancer. Clin Cancer Res 22(12):3005–3015.  https://doi.org/10.1158/1078-0432.CCR-15-2762 CrossRefPubMedGoogle Scholar
  19. 19.
    Leclerc BG, Charlebois R, Chouinard G et al (2016) CD73 expression is an independent prognostic factor in prostate cancer. Clin Cancer Res 22:158–166CrossRefPubMedGoogle Scholar
  20. 20.
    Lindner S, Dahlke K, Sontheimer K et al (2013) Interleukin 21-induced dranzyme B‑expressing B cells infiltrate tumors and regulate T cells. Cancer Res 73:2468–2479CrossRefPubMedGoogle Scholar
  21. 21.
    Mahmoud SM, Lee AH, Paish EC et al (2012) The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat 132:545–553CrossRefPubMedGoogle Scholar
  22. 22.
    Meucci S, Keilholz U, Tinhofer I et al (2016) Mutational load and mutational patterns in relation to age in head and neck cancer. Oncotarget 7:69188–69199CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mittal D, Young A, Stannard K et al (2014) Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res 74:3652–3658CrossRefPubMedGoogle Scholar
  24. 24.
    Mizoguchi A, Mizoguchi E, Takedatsu H et al (2002) Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16:219–230CrossRefPubMedGoogle Scholar
  25. 25.
    Ohta A, Gorelik E, Prasad SJ et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA 103:13132–13137CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Perricone MA, Smith KA, Claussen KA et al (2004) Enhanced efficacy of melanoma vaccines in the absence of B lymphocytes. J Immunother 27:273–281CrossRefPubMedGoogle Scholar
  27. 27.
    Pretscher D, Distel LV, Grabenbauer GG et al (2009) Distribution of immune cells in head and neck cancer: CD8+ T‑cells and CD20+ B‑cells in metastatic lymph nodes are associated with favourable outcome in patients with oro- and hypopharyngeal carcinoma. BMC Cancer 9:292CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rosser EC, Mauri C (2015) Regulatory B cells: origin, phenotype, and function. Immunity 42:607–612CrossRefPubMedGoogle Scholar
  29. 29.
    Sarvaria A, Madrigal JA, Saudemont A (2017) B cell regulation in cancer and anti-tumor immunity. Cell Mol Immunol 14:662–674CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Saze Z, Schuler PJ, Hong CS et al (2013) Adenosine production by human B cells and B cell-mediated suppression of activated T cells. Blood 122:9–18CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Schmidt M, Hellwig B, Hammad S et al (2012) A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors. Clin Cancer Res 18:2695–2703CrossRefPubMedGoogle Scholar
  32. 32.
    Schuler PJ, Harasymczuk M, Schilling B et al (2011) Separation of human CD4+CD39+ T cells by magnetic beads reveals two phenotypically and functionally different subsets. J Immunol Methods 369:59–68CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Schuler PJ, Harasymczuk M, Schilling B et al (2013) Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer. Clin Cancer Res 19:6585–6596CrossRefPubMedGoogle Scholar
  34. 34.
    Schuler PJ, Harasymczuk M, Visus C et al (2014) Phase I dendritic cell p53 peptide vaccine for head and neck cancer. Clin Cancer Res 20:2433–2444CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schuler PJ, Laban S, Doescher J et al (2017) Novel treatment options in head and neck cancer. Oncol Res Treat 40:342–346CrossRefPubMedGoogle Scholar
  36. 36.
    Schuler PJ, Macatangay BJ, Saze Z et al (2013) CD4(+)CD73(+) T cells are associated with lower T‑cell activation and C reactive protein levels and are depleted in HIV-1 infection regardless of viral suppression. AIDS 27:1545–1555CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Schuler PJ, Saze Z, Hong CS et al (2014) Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells. Clin Exp Immunol 177:531–543CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Schuler PJ, Schilling B, Harasymczuk M et al (2012) Phenotypic and functional characteristics of CD4+ CD39+ FOXP3+ and CD4+ CD39+ FOXP3neg T‑cell subsets in cancer patients. Eur J Immunol 42:1876–1885CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Schuler PJ, Westerkamp AM, Kansy BA et al (2017) Adenosine metabolism of human mesenchymal stromal cells isolated from patients with head and neck squamous cell carcinoma. Immunobiology 222:66–74CrossRefPubMedGoogle Scholar
  40. 40.
    Shalapour S, Font-Burgada J, Di Caro G et al (2015) Immunosuppressive plasma cells impede T‑cell-dependent immunogenic chemotherapy. Nature 521:94–98CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shao Y, Lo CM, Ling CC et al (2014) Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett 355:264–272CrossRefPubMedGoogle Scholar
  42. 42.
    Teillaud JL, Dieu-Nosjean MC (2017) Tertiary lymphoid structures: an anti-tumor school for adaptive immune cells and an antibody factory to fight cancer? Front Immunol 8:830CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Turcotte M, Spring K, Pommey S et al (2015) CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res 75:4494–4503CrossRefPubMedGoogle Scholar
  44. 44.
    Vecchio EA, Tan CY, Gregory KJ et al (2016) Ligand-independent adenosine A2B receptor constitutive activity as a promoter of prostate cancer cell proliferation. J Pharmacol Exp Ther 357(1):36–44.  https://doi.org/10.1124/jpet.115.230003 CrossRefPubMedGoogle Scholar
  45. 45.
    Wang WW, Yuan XL, Chen H et al (2015) CD19+CD24hiCD38hiBregs involved in downregulate helper T cells and upregulate regulatory T cells in gastric cancer. Oncotarget 6:33486–33499PubMedPubMedCentralGoogle Scholar
  46. 46.
    Wood O, Woo J, Seumois G et al (2016) Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B‑cell signature when compared to HPV independent tumors. Oncotarget 7:56781–56797CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Zhang C, Xin H, Zhang W et al (2016) CD5 binds to Interleukin-6 and induces a feed-forward loop with the transcription factor STAT3 in B cells to promote cancer. Immunity 44:913–923CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhang Y, Eliav Y, Shin SU et al (2013) B lymphocyte inhibition of anti-tumor response depends on expansion of Treg but is independent of B‑cell IL-10 secretion. Cancer Immunol Immunother 62:87–99CrossRefPubMedGoogle Scholar
  49. 49.
    Zhang Y, Gallastegui N, Rosenblatt JD (2015) Regulatory B cells in anti-tumor immunity. Int Immunol 27:521–530CrossRefPubMedGoogle Scholar
  50. 50.
    Zhang Y, Morgan R, Chen C et al (2016) Mammary-tumor-educated B cells acquire LAP/TGF-beta and PD-L1 expression and suppress anti-tumor immune responses. Int Immunol 28:423–433CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Zhou X, Su YX, Lao XM et al (2016) CD19(+)IL-10(+) regulatory B cells affect survival of tongue squamous cell carcinoma patients and induce resting CD4(+) T cells to CD4(+)Foxp3(+) regulatory T cells. Oral Oncol 53:27–35CrossRefPubMedGoogle Scholar
  52. 52.
    Zhu W, Germain C, Liu Z et al (2015) A high density of tertiary lymphoid structure B cells in lung tumors is associated with increased CD4(+) T cell receptor repertoire clonality. Oncoimmunology 4:e1051922CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ziebart A, Huber U, Jeske SS et al (2017) The influence of chemotherapy on adenosine-producing B cells in patients with head and neck squamous cell carcinoma. Oncotarget 9:5834–5847.  https://doi.org/10.18632/oncotarget.23533 PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Klinik für Hals‑, Nasen‑, Ohrenheilkunde, Kopf- und HalschirurgieUniversitätsklinikum UlmUlmDeutschland

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