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Radio-induced apoptosis of peripheral blood CD8 T lymphocytes is a novel prognostic factor for survival in cervical carcinoma patients

Strahleninduzierte Apoptose von CD8-T-Lymphozyten im peripheren Blut ist ein neuer Prognosefaktor für das Überleben von Zervixkarzinompatientinnen

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Abstract

Background and purpose

A close relationship exists between immune response and tumor behavior. This study aimed to explore the associations between radiation-induced apoptosis (RIA) in peripheral blood lymphocytes (PBL) and clinical pathological variables. Furthermore, it assessed the role of RIA as a prognostic factor for survival in cervical carcinoma patients.

Patients and methods

Between February 1998 and October 2003, 58 consecutive patients with nonmetastatic, localized stage I–II cervical carcinoma who had been treated with radiotherapy (RT) ± chemotherapy were included in this study. Follow-up ended in January 2013. PBL subpopulations were isolated and irradiated with 0, 1, 2 and 8 Gy then incubated for 24, 48 and 72 h. Apoptosis was measured by flow cytometry and the β value, a parameter defining RIA of lymphocytes, was calculated.

Results

Mean follow-up duration was 111.92 ± 40.31 months. Patients with lower CD8 T lymphocyte β values were at a higher risk of local relapse: Exp(B) = 5.137, confidence interval (CI) 95 % = 1.044–25.268, p = 0.044. Similar results were observed for regional relapse: Exp(B) = 8.008, CI 95 % = 1.702–37.679, p = 0.008 and disease relapse: Exp(B) = 6.766, CI 95 % = 1.889–24.238, p = 0.003. In multivariate analysis, only the CD8 T lymphocyte β values were found to be of prognostic significance for local disease-free survival (LDFS, p = 0.049), regional disease-free survival (RDFS, p = 0.002), metastasis-free survival (MFS, p = 0.042), disease-free survival (DFS, p = 0.001) and cause-specific survival (CSS p = 0.028).

Conclusion

For the first time, RIA in CD8 T lymphocytes was demonstrated to be a predictive factor for survival in cervical carcinoma patients.

Zusammenfassung

Hintergrund

Es existiert ein enger Zusammenhang zwischen Immunantwort und Tumorverhalten. Diese Studie hat zum Ziel, das Verhältnis zwischen strahleninduzierter Apoptose („radiation-induced apoptosis“, RIA) von Lymphozyten im peripheren Blut („peripheral blood lymphocytes“, PBL) und klinisch-pathologischen Variablen sowie die Rolle der RIA als Prognoseprädiktor im Bezug auf das Überleben von Zervixkarzinompatientinnen zu untersuchen.

Material und Methode

Zwischen Februar 1998 und Oktober 2003 wurden 58 aufeinanderfolgende Patientinnen mit nichtmetastasiertem, lokalisierten Zervixkarzinom im Stadium I–II, die eine Strahlentherapie ± Chemotherapie erhielten, in diese Studie aufgenommen. Das Follow-up wurde im Januar 2013 abgeschlossen. Die PBL-Untertypen wurden isoliert, mit 0, 1, 2 und 8 Gy bestrahlt und dann für 24, 48 und 72 h inkubiert. Die Apoptose wurde mit Hilfe von Zytometrie und β-Wert, einem Parameter für RIA von Lymphozyten, gemessen.

Ergebnisse

Das mittlere Follow-up der Patientinnen betrug 111,92 ± 40,31 Monate. Patientinnen mit niedrigeren β-Werten der CD8-T-Lymphozyten hatten ein höheres Risiko eines lokalen Rückfalls (Exp(B) = 5,137; 95 %-Konfidenzintervall (KI)  1,044–25,268; p = 0,044). Ähnliche Ergebnisse wurden für regionale Rückfälle (Exp(B) = 8,008; 95 %-KI  1,702–37,679; p = 0,008) und Krankheitsrückfall (Exp(B) = 6,766; 95 %-KI 1,889–24,238; p = 0,003) beobachtet. In der Multivariatenanalyse waren nur die β-Werte der CD8-T-Lymphozyten ein signifikanter Prognosefaktor für ein Überleben ohne lokalen Rückfall (LDFS; p = 0,049), Überleben ohne regionalen Rückfall (RDFS; p = 0,002), Überleben ohne Metastasen (MFS; p = 0,042), krankheitsfreies Überleben (DFS; p = 0,001) und ursachenspezifisches Überleben (CSS; p = 0,028).

Schlussfolgerung

Erstmalig erweist sich die RIA von CD8-T-Lymphozyten als Überlebensprädiktor für Zervixkarzinompatientinnen.

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Abbreviations

Ig:

Immunoglobulin

PE:

Phycoerythrin

PerCP:

Peridinin chlorophyll protein

CD:

Cluster of differentiation

APC:

Allophycocyanin

PI:

Propidium iodide

FITC:

Fluorescein isothiocyanate

NK:

Natural killer cell

PBS:

Phosphate buffered saline

RPMI 1640:

Roswell Park Memorial Institute medium

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Acknowledgment

This work was subsidized by grants: FIS 1035/98, 0855/01. A. Valenciano was supported by an educational grant from the Instituto Canario de Investigación del Cáncer (ICIC). Special thanks to Barbara Leeb for assistance with the German translation.

Compliance with ethical guidelines

Conflict of interest. R. Ordoñez, L. A. Henríquez-Hernández, M. Federico, A. Valenciano, B. Pinar, M. Lloret, E. Bordón, C. Rodríguez-Gallego and P.C. Lara state that there are no conflicts of interest.

All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

All authors have read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr. Negrín, C/ Barranco de La Ballena s/n, 35016, Las Palmas de Gran Canaria, Spain

    R. Ordoñez, L.A. Henríquez-Hernández, M. Federico, B. Pinar, M. Lloret & P.C. Lara

  2. Clinical Sciences Department, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain

    L.A. Henríquez-Hernández, B. Pinar, M. Lloret, E. Bordón & P.C. Lara

  3. Instituto Canario de Investigación del Cáncer (ICIC), Santa Cruz de Tenerife, Spain

    L.A. Henríquez-Hernández, A. Valenciano, B. Pinar, M. Lloret & P.C. Lara

  4. Immunology Department, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain

    C. Rodríguez-Gallego

Authors
  1. R. Ordoñez
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  2. L.A. Henríquez-Hernández
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  3. M. Federico
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  4. A. Valenciano
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  5. B. Pinar
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  6. M. Lloret
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  7. E. Bordón
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  8. C. Rodríguez-Gallego
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  9. P.C. Lara
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Corresponding author

Correspondence to L.A. Henríquez-Hernández.

Additional information

Rafael Ordoñez and Luis Alberto Henríquez-Hernández contributed equally to this work and share first authorship.

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Ordoñez, R., Henríquez-Hernández, L., Federico, M. et al. Radio-induced apoptosis of peripheral blood CD8 T lymphocytes is a novel prognostic factor for survival in cervical carcinoma patients. Strahlenther Onkol 190, 210–216 (2014). https://doi.org/10.1007/s00066-013-0488-x

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