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Ferrata Storti Foundation
Haematologica 2021 Volume 106(3):718-729
Non-Hodgkin Lymphoma
Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma
Matias Autio,1,2,3* Suvi-Katri Leivonen,1,2,3* Oscar Brück,3,4,5 Satu Mustjoki,3,4,5 Judit Mészáros Jørgensen,6 Marja-Liisa Karjalainen-Lindsberg,7
Klaus Beiske,8 Harald Holte,9 Teijo Pellinen10 and Sirpa Leppä1,2,3
1Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 2Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; 3iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland; 4Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland; 5Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; 6Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 7Department of Pathology, Helsinki University Hospital, Helsinki, Finland; 8Department of Pathology, Oslo University Hospital, Oslo, Norway; 9Department of Oncology, and KG Jebsen Centre for B Cell Malignancies, Oslo University Hospital, Oslo, Norway and 10Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland
*MA and S-KL contributed equally as co-first authors.
ABSTRACT
The tumor microenvironment (TME) and limited immune surveil- lance play important roles in lymphoma pathogenesis. Here we aimed to characterize immunological profiles of diffuse large B-cell lymphoma (DLBCL) and predict the outcome in response to immunochemotherapy. We profiled the expression of 730 immune-related genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize T-cell phenotypes, including cytotoxic T cells (CD8, Granzyme B, OX40, Ki67), T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188 patients. We observed a high degree of heterogeneity at the transcriptome level. Correlation matrix analysis identified gene expression signatures with highly correlating genes, the main cluster containing genes for cytolyt- ic factors, immune checkpoint molecules, T cells and macrophages, together named a TME immune cell signature. Immunophenotyping of the distinct cell subsets revealed that a high proportion of immune checkpoint positive T cells translated to unfavorable survival. Together, our results demonstrate that the immunological profile of DLBCL TME is heterogeneous and clini- cally meaningful. This highlights the potential impact of T-cell immune checkpoint in regulating survival and resistance to immunochemotherapy. (Registered at clinicaltrials.gov identifiers: NCT01502982 and NCT01325194.)
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Approximately 60-70% of the patients reach long-term remission in response to a combination of rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) immunochemotherapy.1,2 However, 30-40% of the patients relapse with a dismal prognosis, and a substantial number die from treatment refractory lymphoma.
DLBCL is a result of abnormal B-cell development. Depending on the cell of origin (COO), DLBCL can be divided into germinal-center B-cell like (GCB) and activated B-cell like (ABC) subtypes,3 which vary in their gene expression profiles and clinical courses, the ABC-type DLBCL showing worse outcome.4,5 Recently, the genomic landscape of DLBCL has been thoroughly dissected and several genomic drivers have been established.6-8 The genetic heterogeneity reveals a complex pathogenesis behind DLBCL and highlights a need for personalized therapeutic approaches.
Correspondence:
SIRPA LEPPÄ
sirpa.leppa@helsinki.fi
Received: November 22, 2019. Accepted: February 17, 2020. Pre-published: February 20, 2020.
https://doi.org/10.3324/haematol.2019.243626
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