CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: A multicenter validated retrospective study

Benedikt Fritzsching, Joerg Fellenberg, Linda Moskovszky, Z. Sápi, T. Krenács, Isidro Machado, Johannes Poeschl, Burkhard Lehner, M. Szendrői, Antonio Llombart Bosch, Ludger Bernd, Monika Csóka, Gunhild Mechtersheimer, Volker Ewerbeck, Ralf Kinscherf, Pierre Kunz

Research output: Article

37 Citations (Scopus)

Abstract

Osteosarcoma is the most common primary bone tumor characterized by juvenile onset, tumor heterogeneity, and early pulmonary metastasis. Therapeutic improvement stagnates since more than two decades. Unlike major malignancies, biomarkers as prognostic factors at time of diagnosis are missing. Disease rareness hampers study recruitment of patient numbers sufficient to outweigh tumor heterogeneity. Here, we analyzed in a multicenter cohort the osteosarcoma microenvironment to reduce effects of tumor cell heterogeneity. We hypothesized that quantitative ratios of intratumoral CD8+T-cells to FOXP3+T-cells (CD8+/FOXP3+-ratios) provide strong prognostic information when analyzed by whole-slide imaging in diagnostic biopsies. We followed recommendations-for-tumor-marker-prognosticstudies (REMARK). From 150 included cases, patients with complete treatment were identified and assigned to the discovery (diagnosis before 2004) or the validation cohort (diagnosis 2004–2012). Highly standardized immunohistochemistry of CD8+ and FOXP3+, which was validated by methylation-specific gene analysis, was performed followed by whole-slide analysis and clinical outcome correlations. We observed improved estimated survival in patients with CD8+/FOXP3+-ratios above the median (3.08) compared to patients with lower CD8+/FOXP3+- ratios (p D 0.000001). No patients with a CD8+/FOXP3+-ratio above the third quartile died within the observation period (median follow-up 69 mo). Multivariate analysis demonstrated independence from current prognostic factors including metastasis and response to neoadjuvant chemotherapy. Data from an independent validation cohort confirmed improved survival (p D 0.001) in patients with CD8+/FOXP3+-ratios above 3.08. Multivariate analysis proofed that this observation was also independent from prognostic factors at diagnosis within the validation cohort. Intratumoral CD8+/FOXP3+-ratio in pretreatment biopsies separates patients with prolonged survival from nonsurvivors in osteosarcoma.

Original languageEnglish
Pages (from-to)1-10
Number of pages10
JournalOncoImmunology
Volume4
Issue number3
DOIs
Publication statusPublished - 2015

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Osteosarcoma
Survivors
Retrospective Studies
Neoplasms
Survival
Multivariate Analysis
Neoplasm Metastasis
T-Lymphocytes
Biopsy
Diagnostic Imaging
Tumor Biomarkers
Patient Selection
Methylation
Biomarkers
Immunohistochemistry
Observation
Bone and Bones
Drug Therapy
Lung
Therapeutics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

Cite this

CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors : A multicenter validated retrospective study. / Fritzsching, Benedikt; Fellenberg, Joerg; Moskovszky, Linda; Sápi, Z.; Krenács, T.; Machado, Isidro; Poeschl, Johannes; Lehner, Burkhard; Szendrői, M.; Bosch, Antonio Llombart; Bernd, Ludger; Csóka, Monika; Mechtersheimer, Gunhild; Ewerbeck, Volker; Kinscherf, Ralf; Kunz, Pierre.

In: OncoImmunology, Vol. 4, No. 3, 2015, p. 1-10.

Research output: Article

Fritzsching, B, Fellenberg, J, Moskovszky, L, Sápi, Z, Krenács, T, Machado, I, Poeschl, J, Lehner, B, Szendrői, M, Bosch, AL, Bernd, L, Csóka, M, Mechtersheimer, G, Ewerbeck, V, Kinscherf, R & Kunz, P 2015, 'CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: A multicenter validated retrospective study', OncoImmunology, vol. 4, no. 3, pp. 1-10. https://doi.org/10.4161/2162402X.2014.990800
Fritzsching, Benedikt ; Fellenberg, Joerg ; Moskovszky, Linda ; Sápi, Z. ; Krenács, T. ; Machado, Isidro ; Poeschl, Johannes ; Lehner, Burkhard ; Szendrői, M. ; Bosch, Antonio Llombart ; Bernd, Ludger ; Csóka, Monika ; Mechtersheimer, Gunhild ; Ewerbeck, Volker ; Kinscherf, Ralf ; Kunz, Pierre. / CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors : A multicenter validated retrospective study. In: OncoImmunology. 2015 ; Vol. 4, No. 3. pp. 1-10.
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AU - Krenács, T.

AU - Machado, Isidro

AU - Poeschl, Johannes

AU - Lehner, Burkhard

AU - Szendrői, M.

AU - Bosch, Antonio Llombart

AU - Bernd, Ludger

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AU - Mechtersheimer, Gunhild

AU - Ewerbeck, Volker

AU - Kinscherf, Ralf

AU - Kunz, Pierre

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