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Ferrata Storti Foundation
Haematologica 2019 Volume 104(2):338-346
Non-Hodgkin Lymphoma
T-cell inflamed tumor microenvironment predicts favorable prognosis in primary testicular lymphoma
Suvi-Katri Leivonen,1,2 Marjukka Pollari,1,3 Oscar Brück,4 Teijo Pellinen,5 Matias Autio,1,2 Marja-Liisa Karjalainen-Lindsberg,6 Susanna Mannisto,1,2 Pirkko-Liisa Kellokumpu-Lehtinen,3,7 Olli Kallioniemi,5,8 Satu Mustjoki4,9 and Sirpa Leppä1,2
1Research Program Unit, Medical Faculty, University of Helsinki, Finland; 2Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital, Finland; 3Department of Oncology, Tampere University Hospital, Finland; 4Hematology Research Unit Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, Finland; 5Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland; 6Department of Pathology, Helsinki University Hospital, Finland; 7University of Tampere, Faculty of Medicine and Life Sciences, Finland; 8Science for Life Laboratory, Karolinska Institutet, Department of Oncology and Pathology, Solna, Sweden and 9Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Finland
ABSTRACT
Primary testicular lymphoma is a rare lymphoid malignancy, most often, histologically, representing diffuse large B-cell lymphoma. The tumor microenvironment and limited immune surveillance have a major impact on diffuse large B-cell lymphoma pathogenesis and survival, but the impact on primary testicular lymphoma is unknown. Here, the purpose of the study was to characterize the tumor microen- vironment in primary testicular lymphoma, and associate the findings with outcome. We profiled the expression of 730 immune response genes in 60 primary testicular lymphomas utilizing the Nanostring plat- form, and used multiplex immunohistochemistry to characterize the immune cell phenotypes in the tumor tissue. We identified a gene signa- ture enriched for T-lymphocyte markers differentially expressed between the patients. Low expression of the signature predicted poor outcome independently of the International Prognostic Index (progres- sion-free survival: HR=2.810, 95%CI: 1.228-6.431, P=0.014; overall sur- vival: HR=3.267, 95%CI: 1.406-7.590, P=0.006). The T-lymphocyte sig- nature was associated with outcome also in an independent diffuse large B-cell lymphoma cohort (n=96). Multiplex immunohistochemistry revealed that poor survival of primary testicular lymphoma patients cor- related with low percentage of CD3+CD4+ and CD3+CD8+ tumor-infil- trating lymphocytes (P<0.001). Importantly, patients with a high T-cell inflamed tumor microenvironment had a better response to rituximab- based immunochemotherapy, as compared to other patients. Furthermore, loss of membrane-associated human-leukocyte antigen complexes was frequent and correlated with low T-cell infiltration. Our results demonstrate that a T-cell inflamed tumor microenvironment associates with favorable survival in primary testicular lymphoma. This further highlights the importance of immune escape as a mechanism of treatment failure.
Introduction
Primary testicular lymphoma (PTL) is a rare and aggressive lymphoid malignan- cy; the majority of the cases are diffuse large B-cell lymphomas (DLBCL).1 Patients with PTL have a substantial risk of recurrence and a tendency of lymphoma involvement in additional extranodal sites, such as contralateral testis and the cen- tral nervous system (CNS). Most cases are classified as non-germinal center (non- GC) cell-of-origin subtype, which may partially account for the aggressive nature of the disease. The current standard of care consists of rituximab, cyclophos-
Correspondence:
sirpa.leppa@helsinki.fi
Received: June 18, 2018.
Accepted: September 19, 2018. Pre-published: September 20, 2018.
doi:10.3324/haematol.2018.200105
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/2/338
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