TY - JOUR
T1 - EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity
AU - Gandhi, M. K.
AU - Hoang, T.
AU - Law, S. C.
AU - Brosda, S.
AU - O'Rourke, K.
AU - Tobin, J. W.D.
AU - Vari, F.
AU - Murigneux, V.
AU - Fink, L.
AU - Gunawardana, J.
AU - Gould, C.
AU - Oey, H.
AU - Bednarska, K.
AU - Delecluse, S.
AU - Trappe, R. U.
AU - Merida de Long, L.
AU - Sabdia, M. B.
AU - Bhagat, G.
AU - Hapgood, G.
AU - Blyth, E.
AU - Clancy, L.
AU - Wight, J.
AU - Hawkes, E.
AU - Rimsza, L. M.
AU - Maguire, A.
AU - Bojarczuk, K.
AU - Chapuy, B.
AU - Keane, C.
N1 - Funding Information:
This work was supported by the Leukaemia Foundation and the Mater Foundation (M.K.G.), the University of Queensland Mai Lan Kunzy Scholarship (T.H.), a National Health and Medical Research Council Early Career Fellowship, and a Princess Alexandra Hospital Award and a Cancer Australia and Cancer Cure Grant (ID1161139) (C.K.). The Translational Research Institute is supported by the Australian government. Specimens were provided by AIDS and Cancer Specimen Resource, funded by the National Institutes of Health, National Cancer Institute (UM1CA181255). This publication was also made possible from National Institutes of Health funding through the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke by the following grants: Manhattan HIV Brain Bank (U24MH100931), Texas NeuroAIDS Research Center (U24MH100930), National Neurological AIDS Bank (U24MH100929), California NeuroAIDS Tissue Network (U24MH100928), and Data Coordinating Center (U24MH100925). The contents are solely the responsibility of the authors and do not necessarily represent the official view of the NeuroAIDS National Tissue Collection or National Institutes of Health.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/3/18
Y1 - 2021/3/18
N2 - Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.
AB - Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV− HIV− PCNSL and 2 EBV− HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV− PCNSL. As with prior studies, EBV− HIV− PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV− PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV− HIV− PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.
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U2 - 10.1182/blood.2020008520
DO - 10.1182/blood.2020008520
M3 - Article
C2 - 33202420
AN - SCOPUS:85102844006
SN - 0006-4971
VL - 137
SP - 1468
EP - 1477
JO - Blood
JF - Blood
IS - 11
ER -