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Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients

Auswirkungen von definitiver und Salvage-Strahlentherapie auf die Verteilung von Lymphozytensubpopulationen bei Prostatakarzinompatienten

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Abstract

Background

Radiotherapy (RT) is an established treatment for patients with primary and recurrent prostate cancer. Herein, the effects of definitive and salvage RT on the composition of lymphocyte subpopulations were investigated in patients with prostate cancer to study potential immune effects.

Patients and methods

A total of 33 prostate cancer patients were treated with definitive (n = 10) or salvage RT (n = 23) after biochemical relapse. The absolute number of lymphocytes and the distribution of lymphocyte subpopulations were analyzed by multiparameter flow cytometry before RT, at the end of RT, and in the follow-up period.

Results

Absolute lymphocyte counts decreased significantly after RT in both patient groups and a significant drop was observed in the percentage of B cells directly after RT from 10.1 ± 1.3 to 6.0 ± 0.7% in patients with definitive RT and from 9.2 ± 0.8 to 5.8 ± 0.7% in patients with salvage RT. In contrast, the percentages of T and natural killer (NK) cells remained unaltered directly after RT in both patient groups. However, 1 year after RT, the percentage of CD3+ T cells was significantly lower in patients with definitive and salvage RT. The percentage of regulatory T cells was slightly upregulated in primary prostate cancer patients after definitive RT, but not after salvage RT.

Conclusion

Definitive and salvage RT exert similar effects on the composition of lymphocyte subpopulations in prostate cancer patients. Total lymphocyte counts are lower in both patient groups compared to healthy controls and further decreased after RT. B cells are more sensitive to definitive and salvage RT than T and NK cells.

Zusammenfassung

Hintergrund

Die Strahlentherapie (RT) ist eine bewährte Behandlung bim primären und rezidivierten Prostatakarzinoms. In dieser Studie wurde der Einfluss einer definitiven und Salvage RT auf die Zusammensetzung der Lymphozytensubpopulationen verglichen, um potenzielle Immuneffekte einer RT zu analysieren.

Patienten und Methoden

In die Studie wurden 33 Prostatakarzinompatienten eingeschlossen. Mit definitiver RT wurden 10 Patienten mit primärem Prostatakarzinom behandelt; 23 Patienten erhielten eine Salvage-RT nach biochemischem Rezidiv. Die absoluten Lymphozytenzahlen sowie die der Subpopulationen wurden vor RT, am Ende der RT und während des Follow-ups mittels Durchflusszytometrie analysiert.

Ergebnisse

Die absoluten Lymphozytenzahlen gingen in beiden Gruppen signifikant zurück. Direkt nach RT zeigte sich ein signifikanter Abfall der B‑Lymphozyten von 10,1 ± 1,3 % auf 6,0 ± 0,7 % bei Patienten mit definitiver RT und von 9,2 ± 0,8 % auf 5,8 ± 0,7 % bei Patienten mit Salvage-RT. Im Gegensatz dazu blieb der Anteil von T‑ und natürlichen Killerzellen (NK-Zellen) direkt nach RT in beiden Gruppen unverändert. Ein Jahr nach definitiver und Salvage-RT zeigte sich jedoch ein signifikanter Abfall der CD3+-T-Zellen. Der Anteil regulatorischer T‑Zellen war bei Patienten mit primärem Prostatakarzinom nach definitiver RT leicht erhöht, nicht jedoch nach Salvage-RT.

Schlussfolgerung

Die Verteilung der Lymphozytensubpopulationen nach definitiver oder Salvage-RT unterscheidet sich nicht signifikant in den Patientengruppen. Beide Gruppen weisen im Vergleich zu gesunden Kontrollen erniedrigte Gesamtlymphozytenwerte auf, die nach RT noch weiter absinken. B‑Zellen verhalten sich gegenüber einer definitiven und Salvage-RT sensibler als T‑ und NK-Zellen.

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References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30. doi:10.3322/caac.21332

    Article  PubMed  Google Scholar 

  2. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403. doi:10.1016/j.ejca.2012.12.027

    Article  CAS  PubMed  Google Scholar 

  3. Pinkawa M, Piroth MD, Holy R, Djukic V, Klotz J, Krenkel B, Eble MJ (2011) Combination of dose escalation with technological advances (intensity-modulated and image-guided radiotherapy) is not associated with increased morbidity for patients with prostate cancer. Strahlenther Onkol 187(8):479–484. doi:10.1007/s00066-011-2249-z

    Article  PubMed  Google Scholar 

  4. Catton C, Milosevic M (2003) Salvage radiotherapy following radical prostatectomy. World J Urol 21(4):243–252. doi:10.1007/s00345-003-0360-1

    Article  PubMed  Google Scholar 

  5. Trock BJ, Han M, Freedland SJ, Humphreys EB, DeWeese TL, Partin AW, Walsh PC (2008) Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA 299(23):2760–2769. doi:10.1001/jama.299.23.2760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pinkawa M (2015) Recent advances in definitive radiotherapy for prostate cancer. Eur Med J Oncol 3(1):41–48

    Google Scholar 

  7. Budach W, Sachkerer I (2014) Dose escalation: an update on randomised clinical trials. In: Geinitz R III (ed) Radiotherapy in prostate cancer. Medical radiology. Springer, Berlin, pp 89–93

    Google Scholar 

  8. Hou Z, Li G, Bai S (2015) High dose versus conventional dose in external beam radiotherapy of prostate cancer: a meta-analysis of long-term follow-up. J Cancer Res Clin Oncol 141(6):1063–1071. doi:10.1007/s00432-014-1813-1

    Article  CAS  PubMed  Google Scholar 

  9. Freedland SJ, Sutter ME, Dorey F, Aronson WJ (2003) Defining the ideal cutpoint for determining PSA recurrence after radical prostatectomy. Prostate-specific antigen. Urology 61(2):365–369

    Article  PubMed  Google Scholar 

  10. Geinitz H, Riegel MG, Thamm R, Astner ST, Lewerenz C, Zimmermann F, Molls M, Nieder C (2012) Outcome after conformal salvage radiotherapy in patients with rising prostate-specific antigen levels after radical prostatectomy. Int J Radiat Oncol Biol Phys 82(5):1930–1937. doi:10.1016/j.ijrobp.2011.03.003

    Article  PubMed  Google Scholar 

  11. Jereczek-Fossa BA, Orecchia R (2007) Evidence-based radiation oncology: definitive, adjuvant and salvage radiotherapy for non-metastatic prostate cancer. Radiother Oncol 84(2):197–215. doi:10.1016/j.radonc.2007.04.013

    Article  PubMed  Google Scholar 

  12. King CR (2012) The timing of salvage radiotherapy after radical prostatectomy: a systematic review. Int J Radiat Oncol Biol Phys 84(1):104–111. doi:10.1016/j.ijrobp.2011.10.069

    Article  PubMed  Google Scholar 

  13. Izawa JI (2009) Salvage radiotherapy after radical prostatectomy. Can Urol Assoc J 3(3):245–250

    PubMed  PubMed Central  Google Scholar 

  14. Malone S, Croke J, Roustan-Delatour N, Belanger E, Avruch L, Malone C, Morash C, Kayser C, Underhill K, Li Y, Malone K, Nyiri B, Spaans J (2012) Postoperative radiotherapy for prostate cancer: a comparison of four consensus guidelines and dosimetric evaluation of 3D-CRT versus tomotherapy IMRT. Int J Radiat Oncol Biol Phys 84(3):725–732. doi:10.1016/j.ijrobp.2011.12.081

    Article  PubMed  Google Scholar 

  15. Schaue D, Xie MW, Ratikan JA, McBride WH (2012) Regulatory T cells in radiotherapeutic responses. Front Oncol 2:90. doi:10.3389/fonc.2012.00090

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Demaria S, Golden EB, Formenti SC (2015) Role of local radiation therapy in cancer immunotherapy. JAMA Oncol 1(9):1325–1332. doi:10.1001/jamaoncol.2015.2756

    Article  PubMed  Google Scholar 

  17. Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY (2013) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med 210(11):2435–2466. doi:10.1084/jem.20130762

    Article  PubMed  PubMed Central  Google Scholar 

  18. Spiotto M, Fu YX, Weichselbaum RR (2016) The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci Immunol 1(3). doi:10.1126/sciimmunol.aag1266

    PubMed  PubMed Central  Google Scholar 

  19. Formenti SC, Demaria S (2009) Systemic effects of local radiotherapy. Lancet Oncol 10(7):718–726. doi:10.1016/s1470-2045(09)70082-8

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sage EK, Schmid TE, Sedelmayr M, Gehrmann M, Geinitz H, Duma MN, Combs SE, Multhoff G (2016) Comparative analysis of the effects of radiotherapy versus radiotherapy after adjuvant chemotherapy on the composition of lymphocyte subpopulations in breast cancer patients. Radiother Oncol 118(1):176–180. doi:10.1016/j.radonc.2015.11.016

    Article  PubMed  Google Scholar 

  21. Deloch L, Derer A, Hartmann J, Frey B, Fietkau R, Gaipl US (2016) Modern radiotherapy concepts and the impact of radiation on immune activation. Front Oncol 6:141. doi:10.3389/fonc.2016.00141

    Article  PubMed  PubMed Central  Google Scholar 

  22. Multhoff G, Gaipl US, Niedermann G (2012) The role of radiotherapy in the induction of antitumor immune responses. Strahlenther Onkol 188(Suppl 3):312–315. doi:10.1007/s00066-012-0206-0

    Article  PubMed  Google Scholar 

  23. Frey B, Rubner Y, Wunderlich R, Weiss EM, Pockley AG, Fietkau R, Gaipl US (2012) Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation – implications for cancer therapies. Curr Med Chem 19(12):1751–1764

    Article  CAS  PubMed  Google Scholar 

  24. Cihan YB, Arslan A, Ergul MA (2013) Subtypes of white blood cells in patients with prostate cancer or benign prostatic hyperplasia and healthy individuals. Asian Pac J Cancer Prev 14(8):4779–4783

    Article  PubMed  Google Scholar 

  25. Pinkawa M, Ribbing C, Djukic V, Klotz J, Holy R, Eble MJ (2015) Early hematologic changes during prostate cancer radiotherapy predictive for late urinary and bowel toxicity. Strahlenther Onkol 191(10):771–777. doi:10.1007/s00066-015-0841-3

    Article  PubMed  Google Scholar 

  26. Gershkevitsh E, Rosenberg I, Dearnaley DP, Trott KR (1999) Bone marrow doses and leukaemia risk in radiotherapy of prostate cancer. Radiother Oncol 53(3):189–197

    Article  CAS  PubMed  Google Scholar 

  27. Stöver I, Feyer P (2010) Praxismanual Strahlentherapie. Springer, Berlin, p 31

    Book  Google Scholar 

  28. Chapel H, Haeney M, Misbah S, Snowden N (2014) Essentials of clinical immunology, 6th edn. Wiley-Blackwell, Chichester

    Google Scholar 

  29. Multhoff G, Meier T, Botzler C, Wiesnet M, Allenbacher A, Wilmanns W, Issels RD (1995) Differential effects of ifosfamide on the capacity of cytotoxic T lymphocytes and natural killer cells to lyse their target cells correlate with intracellular glutathione levels. Blood 85(8):2124–2131

    CAS  PubMed  Google Scholar 

  30. Belka C, Ottinger H, Kreuzfelder E, Weinmann M, Lindemann M, Lepple-Wienhues A, Budach W, Grosse-Wilde H, Bamberg M (1999) Impact of localized radiotherapy on blood immune cells counts and function in humans. Radiother Oncol 50(2):199–204

    Article  CAS  PubMed  Google Scholar 

  31. Sotosek S, Sotosek Tokmadzic V, Mrakovcic-Sutic I, Tomas MI, Dominovic M, Tulic V, Sutic I, Maricic A, Sokolic J, Sustic A (2011) Comparative study of frequency of different lymphocytes subpopulation in peripheral blood of patients with prostate cancer and benign prostatic hyperplasia. Wien Klin Wochenschr 123(23–24):718–725. doi:10.1007/s00508-011-0096-7

    Article  CAS  PubMed  Google Scholar 

  32. Nardone V, Botta C, Caraglia M, Martino EC, Ambrosio MR, Carfagno T, Tini P, Semeraro L, Misso G, Grimaldi A, Boccellino M, Facchini G, Berretta M, Vischi G, Rocca BJ, Barone A, Tassone P, Tagliaferri P, Del Vecchio MT, Pirtoli L, Correale P (2016) Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse. Cancer Biol Ther. doi:10.1080/15384047.2016.1235666

    PubMed  Google Scholar 

  33. Ness N, Andersen S, Valkov A, Nordby Y, Donnem T, Al-Saad S, Busund LT, Bremnes RM, Richardsen E (2014) Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer. Prostate 74(14):1452–1461. doi:10.1002/pros.22862

    Article  CAS  PubMed  Google Scholar 

  34. Tao CJ, Chen YY, Jiang F, Feng XL, Jin QF, Jin T, Piao YF, Chen XZ (2016) A prognostic model combining CD4/CD8 ratio and N stage predicts the risk of distant metastasis for patients with nasopharyngeal carcinoma treated by intensity modulated radiotherapy. Oncotarget 7(29):46653–46661. doi:10.18632/oncotarget.9695

    PubMed  PubMed Central  Google Scholar 

  35. Ordonez R, Henriquez-Hernandez LA, Federico M, Valenciano A, Pinar B, Lloret M, Bordon E, Rodriguez-Gallego C, Lara PC (2014) Radio-induced apoptosis of peripheral blood CD8 T lymphocytes is a novel prognostic factor for survival in cervical carcinoma patients. Strahlenther Onkol 190(2):210–216. doi:10.1007/s00066-013-0488-x

    Article  CAS  PubMed  Google Scholar 

  36. McClatchey KD (2002) Clinical laboratory medicine, 2nd edn. Lippincott Wiliams & Wilkins, Philadelphia

    Google Scholar 

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Acknowledgements

The authors thank Bernhard Haller for support with statistical analysis of the data.

Funding

This work was supported by EU-CELLEUROPE (315963); BMBF (Strahlenkompetenz, 02NUK038A; Innovative Therapies, 01GU0823; NSCLC, 16GW0030), German Cancer Consortium Radiation Oncology Group (DKTK-ROG); the DFG Cluster of Excellence: Munich Centre for Advanced Photonics (MAP); DFG SFB 824/2; INST 95/980-1 FUGG; INST 411/37-1 FUGG irradiation devices. Eva Sage was supported by the Medical Faculty of TUM as a fellow of the doctoral program “Translationale Medizin.” This work was supported by the German Research Foundation (DFG) and the Technische Universität München within the Open Access Publishing funding program.

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Authors and Affiliations

  1. Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Munich, Germany

    Eva K. Sage, Thomas E. Schmid, Mathias Gehrmann, Michael Sedelmayr, Marciana N. Duma, Stephanie E. Combs & Gabriele Multhoff

  2. Department of Radiation Sciences (DRS), Institute of Innovate Radiotherapy (iRT), HelmholtzZentrum München, Munich, Germany

    Thomas E. Schmid, Marciana N. Duma, Stephanie E. Combs & Gabriele Multhoff

  3. Partner Site Munich, Deutsches Konsortium für Translationale Krebsforschung (DKTK), Munich, Germany

    Thomas E. Schmid, Stephanie E. Combs & Gabriele Multhoff

  4. Department of Radiation Oncology, Ordensklinikum Linz, Krankenhaus der Barmherzigen Schwestern and Medical Faculty, Johannes Kepler University, Linz, Austria

    Hans Geinitz

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  1. Eva K. Sage
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Correspondence to Gabriele Multhoff.

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Conflict of interest

E.K. Sage, T.E. Schmid, H. Geinitz, M. Gehrmann, M. Sedelmayr, M.N. Duma, S.E. Combs, and G. Multhoff declare that they have no competing interests.

Caption Electronic Supplementary Material

66_2017_1144_MOESM1_ESM.docx

Supplementary table 1: List of all antibody combinations and chromophores which were used in the study. Antibody stainings which did not show any significant changes in the patient samples during the course of analysis were not shown in the results part.

66_2017_1144_MOESM2_ESM.jpg

Supplementary figure 1: Schematic representation of the gating procedure of the flow cytometry data. R1 lymphocyte gate, R2 granolocytes, R3 monocytes.

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Sage, E.K., Schmid, T.E., Geinitz, H. et al. Effects of definitive and salvage radiotherapy on the distribution of lymphocyte subpopulations in prostate cancer patients. Strahlenther Onkol 193, 648–655 (2017). https://doi.org/10.1007/s00066-017-1144-7

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