title: Expression of CCL21 in Ewing sarcoma shows an inverse correlation with metastases and is a candidate target for immunotherapy.
abstract: Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The CCL21 RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples. In the tumor samples, this was correlated with the number and CD4(+)/CD8(+) ratio of infiltrating T cells and clinical parameters. Higher RNA expression levels of CCL21 significantly correlated with a lower CD4(+)/CD8(+) T cell ratio (P = 0.009), good chemotherapeutic response (P = 0.01) and improved outcome (P < 0.001). In patients with metastases, CCL21 expression was significantly lower than in patients without (P < 0.0005). CCL21 expression was significantly higher in Ewing sarcoma tissue samples compared to cell lines (P < 0.01), implying the involvement of a stromal factor. Protein expression analysis of CCL21 and its receptor CCR7 in 24 therapy-naïve tumors showed that there was no expression in all bar one Ewing sarcoma cells. In conclusion, CCL21 is expressed in clinical Ewing sarcoma samples by nontumor-infiltrating immune cells. The observed positive correlation with survival implies that CCL21 might be a potential prognostic marker for Ewing sarcoma and marks the potential of CCL21 immunotherapy for use in Ewing sarcoma.
authors.affiliation: Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Laurens G L
authors.initials: LG
authors.lastname: Sand
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Berghuis
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.affiliation: Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. P.C.W.Hogendoorn@lumc.nl.
authors.forename: Pancras C W
authors.initials: PC
authors.lastname: Hogendoorn
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D054421:Chemokine CCL21 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007167:Immunotherapy; D008297:Male; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: C515478:CCL21 protein, human; D054421:Chemokine CCL21
keywords: Bone tumor; Immune response; Immunotherapy; Soft tissue tumor; Tumor microenvironment