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Epstein–Barr virus recruits PDL1-positive cells at the microenvironment in pediatric Hodgkin lymphoma

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Abstract

Background

Classic Hodgkin lymphoma (cHL) is a lymphoid malignancy in which the microenvironment, where the neoplastic cells are immersed, contributes to the lymphomagenesis process. Epstein–Barr virus (EBV) presence also influences cHL microenvironment composition and contributes to pathogenesis. An increase in PDL1 expression in tumor cells and at the microenvironment was demonstrated in adult cHL. Therefore, our aim was to assess PD1/PDL1 pathway and EBV influence on this pathway in pediatric cHL, given that in Argentina, our group proved a higher incidence of EBV-associated pediatric lymphoma in children.

Methods

For that purpose, EBV presence was assessed by in situ hybridization, whereas PD1 and PDL1 expressions were studied by immunohistochemistry. PDL1 genetic alterations were analyzed by FISH, and survival was evaluated for PD1 and PDL1 expressions.

Results

EBV presence demonstrated no influence neither on PD1 expression at the microenvironment nor on PDL1 expression at HRS tumor cells. Unexpectedly, only 38% pediatric cHL displayed PDL1 genetic alterations by FISH, and no difference was observed regarding EBV presence. However, in EBV-related cHL cases, a higher number of PDL1 + cells were detected at the microenvironment.

Conclusion

Even though a high cytotoxic environment was previously described in EBV-related pediatric cHL, it might be counterbalanced by an immunoregulatory micro-environmental PDL1 + niche. This regulation may render a cytotoxic milieu that unsuccessfully try to eliminate EBV + Hodgkin Reed Sternberg tumor cells in pediatric patients.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank Barbara Cao; Silvana Romero; Cristina Pabes and Maria Jose Andrade (Histopathological Laboratory, at the Ricardo Gutierrez Children’s Hospital) for their helpful histotechnical work.

Funding

This study was supported in part by grants from National Agency for Science and Technology Promotion (PICT 2015 n° 1533- PID clinic n°048- PICT 2017 1554). CP, DME and PMV are members of the CONICET Research Career Program. JO is a CONICET doctoral fellow.

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Authors and Affiliations

  1. Molecular Biology Laboratory, Pathology Divison, Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP), CONICET-GCBA, Hospital de Niños R. Gutiérrez, Gallo 1330, C1425EFD, Buenos Aires, Argentina

    O. Jimenez, M. V. Preciado, E. De Matteo & P. Chabay

  2. Pathology Division, Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina

    S. Colli & E. De Matteo

  3. Oncology Division, Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina

    M. Garcia Lombardi

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  1. O. Jimenez
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  2. S. Colli
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  3. M. Garcia Lombardi
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  4. M. V. Preciado
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  5. E. De Matteo
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  6. P. Chabay
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Contributions

CP conceived of the study and its design, drafted the manuscript and acquired funding. JO and CS performed the experiments, the analysis and interpretation of data. GLM, DME and PMV participated in its coordination and modification. All authors read and approved the final manuscript.

Corresponding author

Correspondence to P. Chabay.

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The authors declare that they have no competing interests.

Ethical approval and consent to participate

Institutional guidelines regarding human experimentation were followed, according to the Helsinki Declaration of 1975. The protocol was approved by the Ethical Committee of Ricardo Gutierrez Children Hospital, and written informed assent and consent was obtained from all patients or patient´s parents depending on age.

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262_2020_2787_MOESM1_ESM.pdf

Supplementary Fig. 1: Event-free survival (EFS) analysis to IL10 + cells at microenvironment (cut off 50th percentile) (A) and TGFβ + cells at the microenvironment (cut off 50th percentile) (B) (PDF 70 KB)

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Jimenez, O., Colli, S., Garcia Lombardi, M. et al. Epstein–Barr virus recruits PDL1-positive cells at the microenvironment in pediatric Hodgkin lymphoma. Cancer Immunol Immunother 70, 1519–1526 (2021). https://doi.org/10.1007/s00262-020-02787-2

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  • DOI: https://doi.org/10.1007/s00262-020-02787-2

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