TY - JOUR
T1 - Predictive Value of CD8 Expression and FoxP3 Methylation in Nasopharyngeal Carcinoma Patients Treated with Chemoradiotherapy in a Non-endemic Area
AU - Muraro, E.
AU - Vaccher, E.
AU - Furlan, C.
AU - Fratta, E.
AU - Fanetti, G.
AU - Fae’, D. A.
AU - Martorelli, D.
AU - Cangemi, M.
AU - Polesel, J.
AU - Navarria, F.
AU - Gobitti, C.
AU - Comaro, E.
AU - Scaini, C.
AU - Pratesi, C.
AU - Zanussi, S.
AU - Lupato, V.
AU - Grando, G.
AU - Giacomarra, V.
AU - Sulfaro, S.
AU - Barzan, L.
AU - Dolcetti, R.
AU - Steffan, A.
AU - Canzonieri, V.
AU - Franchin, G.
N1 - Funding Information:
The authors thank the patients, the flow cytometry core facility of CRO Aviano National Cancer Institute, the other investigators participating in the study, and Miss S. Colussi for editing the manuscript. This work was supported by grants from the CRO Aviano National Cancer Institute (5 × 1000 Institutional Grant).
Publisher Copyright:
© 2020, Arányi Lajos Foundation.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Undifferentiated Nasopharyngeal Carcinoma (UNPC) is associated with Epstein-Barr Virus (EBV) and characterized by an abundant immune infiltrate potentially influencing the prognosis. Thus, we retrospectively assessed the significance of immunosuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area, and monitored the variation of systemic EBV-specific immunity before and after chemoradiotherapy (CRT). DNA and RNA were extracted from diagnostic biopsies obtained by tumor and adjacent mucosa from 63 consecutive EBV+ UNPC patients who underwent radical CRT. Among these patients 11 relapsed within 2 years. The expression of the EBV-derived UNPC-specific BARF1 gene and several immune-related genes was monitored through quantitative RT-PCR and methylation-specific PCR analyses. Peripheral T cell responses against EBV and BARF1 were measured in 14 patients (7 relapses) through IFN-γ ELISPOT assay. We found significantly higher expression levels of BARF1, CD8, IFN-γ, IDO, PD-L1, and PD-1 in UNPC samples compared to healthy tissues. CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years. We observed a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we noticed a significant decrease in EBV- and BARF1-specific T-cells after CRT only in relapsing patients. Our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and may allow an early identification of patients who could benefit from the addition of immune modulating strategies to improve first line CRT.
AB - Undifferentiated Nasopharyngeal Carcinoma (UNPC) is associated with Epstein-Barr Virus (EBV) and characterized by an abundant immune infiltrate potentially influencing the prognosis. Thus, we retrospectively assessed the significance of immunosuppression in the UNPC microenvironment as prognostic biomarker of treatment failure in a non-endemic area, and monitored the variation of systemic EBV-specific immunity before and after chemoradiotherapy (CRT). DNA and RNA were extracted from diagnostic biopsies obtained by tumor and adjacent mucosa from 63 consecutive EBV+ UNPC patients who underwent radical CRT. Among these patients 11 relapsed within 2 years. The expression of the EBV-derived UNPC-specific BARF1 gene and several immune-related genes was monitored through quantitative RT-PCR and methylation-specific PCR analyses. Peripheral T cell responses against EBV and BARF1 were measured in 14 patients (7 relapses) through IFN-γ ELISPOT assay. We found significantly higher expression levels of BARF1, CD8, IFN-γ, IDO, PD-L1, and PD-1 in UNPC samples compared to healthy tissues. CD8 expression was significantly reduced in both tumor and healthy tissues in UNPC patients who relapsed within two years. We observed a hypomethylated FOXP3 intron 1 exclusively in relapsed UNPC patients. Finally, we noticed a significant decrease in EBV- and BARF1-specific T-cells after CRT only in relapsing patients. Our data suggest that a high level of immunosuppression (low CD8, hypomethylated FoxP3) in UNPC microenvironment may predict treatment failure and may allow an early identification of patients who could benefit from the addition of immune modulating strategies to improve first line CRT.
KW - CD8
KW - Chemoradiotherapy
KW - EBV-specific immunity
KW - FoxP3
KW - Immunosuppression
KW - Nasopharyngeal carcinoma
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UR - http://www.scopus.com/inward/citedby.url?scp=85086780032&partnerID=8YFLogxK
U2 - 10.1007/s12253-020-00859-3
DO - 10.1007/s12253-020-00859-3
M3 - Article
C2 - 32564263
AN - SCOPUS:85086780032
VL - 26
SP - 2459
EP - 2467
JO - Pathology and Oncology Research
JF - Pathology and Oncology Research
SN - 1219-4956
IS - 4
ER -