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Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas

Abstract

Primary central nervous system diffuse large B cell lymphoma (PCNS-DLBCL) is a rare and aggressive entity of diffuse large B cell lymphoma (DLBCL). Elements of the tumour microenvironment (TME) including tumour-infiltrating lymphocytes (TILs) and tumour-associated macrophages (TAMs) have been associated with survival in DLBCL but their composition and prognostic impact in PCNS-DLBCL are unknown. Programmed cell death-1 (PD1)/programmed death-ligand 1 (PD-L1) immune checkpoint may represent a therapeutic option. Here, we aimed to characterise PD1/PDL1 immune checkpoints and the composition of the TME in PCNS-DLBCL. We collected tumour tissue and clinical data from 57 PCNS-DLBCL and used immunohistochemistry to examine TAMs (CD68, CD163), TILs (CD3, CD4, CD8, PD1) and tumour B cells (PAX5/PDL1 double stains, PDL1). The PDL1 gene was evaluated by fluorescence in situ hybridization (FISH). PAX5/PDL1 identified PDL1 expression by tumour B cells in 10/57 cases (17.5%). PDL1 gene translocation was a recurrent cytogenetic alteration in PNCS-DLBCL (8/47.17%) and was correlated with PDL1 positive expression in tumour B cells. The TME consisted predominantly of CD163 (+) M2 TAMs and CD8 (+) TILs. Most TAMs expressed PDL1 and most TILs expressed PD1. The density of TAMs and TILs did not associate with outcome. We showed that expression of PD1 on TILs and PDL1 on TAMs, but not the expression of PDL1 on tumour B cells was correlated with better prognosis. These findings support a significant role of TME composition and PD1/PDL1 crosstalk in PCNS-DLBCL pathogenesis and bring new insights to the targeted therapy of this aggressive lymphoma.

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Author information

Vanessa Szablewski, Melissa Alame, Valérie Costes-Martineau, Valérie Rigau and Valère Cacheux designed the research project. Vanessa Szablewski, Marion Pirel, Valérie Rigau, Luc Durand and Valérie Costes-Martineau evaluated the histological and immunohistochemical findings. Vanessa Szablewski, Melissa Alame, Laura De Oliveira, Alicia Tourneret and Valère Cacheux evaluated the cytogenetic findings. Vanessa Szablewski and Melissa Alame obtained data and wrote the main part of the manuscript. Marion Pirel, Valérie Costes-Martineau, Luc Bauchet, Michel Fabbro, Pascal Roger, Samia Gonzalez, Luc Durand, Laura De Oliveira, Alicia Tourneret Tempier, Valérie Rigau and Valère Cacheux reviewed the draft with critical comments.

Correspondence to Vanessa Szablewski.

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This study was carried out in agreements with the Declaration of Helsinki and was approved by the Centre des Ressources Biologiques (CRB) of the Centre Hospitalo Universitaire (CHU) of Montpellier, France.

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Written informed consent for the study was obtained from the patient.

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Alame, M., Pirel, M., Costes-Martineau, V. et al. Characterisation of tumour microenvironment and immune checkpoints in primary central nervous system diffuse large B cell lymphomas. Virchows Arch (2019). https://doi.org/10.1007/s00428-019-02695-6

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Keywords

  • Primary central nervous system diffuse large B cell lymphoma
  • Tumour microenvironment
  • Immune checkpoints
  • PDL1