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Haematologica 2018 Volume 103(11):1908-1914
1Research Program Unit, Faculty of Medicine, University of Helsinki, Finland; 2Department of Oncology, Tampere University Hospital, Finland; 3Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Finland; 4Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland; 5Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital, Finland; 6Department of Pathology, Helsinki University Hospital, Finland; 7Science for Life Laboratory, Karolinska Institutet, Department of Oncology and Pathology, Solna, Sweden; 8Faculty of Medicine and Life Sciences, University of Tampere, Finland; 9Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Finland
Ferrata Storti Foundation
Non-Hodgkin Lymphoma
PD-L1+ tumor-associated macrophages and PD-1+ tumor-infiltrating lymphocytes predict survival in primary testicular lymphoma
Marjukka Pollari,1,2 Oscar Brück,3 Teijo Pellinen,4 Pauli Vähämurto,1,5 Marja-Liisa Karjalainen-Lindsberg,6 Susanna Mannisto,1,5 Olli Kallioniemi,4,7 Pirkko-Liisa Kellokumpu-Lehtinen,2,8 Satu Mustjoki,3,9 Suvi-Katri Leivonen1,5 and Sirpa Leppä1,5
ABSTRACT
Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrat- ing lymphocytes have been associated with survival in diffuse large B- cell lymphoma, but their prognostic impact in primary testicular lym- phoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demon- strate that a large proportion of macrophages (median 41%, range 0.08- 99%) and lymphoma cells (median 34%, range 0.1-100%) express PD- L1. The quantity of PD-L1+CD68+ macrophages correlates positively with the amount of PD-1+ lymphocytes, and a high proportion of either PD-L1+CD68+ macrophages or PD-1+CD4+ and PD-1+CD8+ T cells trans- lates into favorable survival. In contrast, the number of PD-L1+ lym- phoma cells or PD-L1– macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1+CD68+ macrophage and PD-1+ lymphocyte contents remain as independent prognostic factors for sur- vival. In conclusion, high PD-L1+CD68+ macrophage and PD-1+ lympho- cyte contents predict favorable survival in patients with primary testic- ular lymphoma. The findings implicate that the tumor microenviron- ment and PD-1 – PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted thera- py of primary testicular lymphoma.
Introduction
Primary testicular lymphoma (PTL) is a rare and aggressive lymphoid malignancy affecting mainly elderly men. The biology of PTL is beginning to emerge,1-7 and the outcome has improved with the addition of anthracycline-based chemotherapy, central nervous system (CNS) targeted therapy and irradiation of the contralateral testis.8-10 The majority of PTLs represent diffuse large B-cell lymphoma (DLBCL) displaying more often non-germinal center B-cell (GCB) than GCB-like signatures.11 Somatic mutations in NF-κ-B pathway genes, such as MYD88 and CD79B, as well as rearrangements of programmed cell death ligand (PD-L) -1 and -2 genes, have been shown to be enriched in PTL.2,4 In addition, two stromal signatures associated
Correspondence:
sirpa.leppa@helsinki.fi
Received: May 6, 2018. Accepted: July 16, 2018. Pre-published: July 19, 2018.
doi:10.3324/haematol.2018.197194
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1908
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