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1552 Tumor Microenvironment and It’s Prognostic Value Is Different in Testicular and Systemic Diffuse Large B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational–Non-Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, immunology, Biological Processes, Technology and Procedures, profiling, pathogenesis
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Marjukka Pollari, MD, PhD1,2*, Matias Autio1,3*, Oscar Brück, MD, PhD4*, Teijo Pellinen, PhD5*, Suvi-Katri Leivonen, PhD1,3 and Sirpa Leppa, MD, PhD3,6

1Research Program Unit, Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
2Department of Oncology, Tampere University Hospital, Tampere, Finland
3Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
4Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
5Institute for Molecular Medicine Finland, Helsinki, Finland
6Research Programs Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland

Testicular diffuse large B-cell lymphoma (T-DLBCL) is an aggressive lymphoid cancer with distinct clinical and biological features. Majority of the cases represent non-GCB phenotype, but the genetic landscape with frequent aberrations in MYD88, NFKBIZ, PDCD1LG2, and CD274 differ from systemic non-GCB DLBCL and highlight the significance of immune-escape and tumor microenvironment (TME).

We have previously shown that high T-cell gene expression signature and high tumor-infiltrating lymphocyte (TIL) content translate to better survival in testicular but not in systemic DLBCL. We have also described a subpopulation of T-bet+FoxP3+ Tregs that have a significant adverse impact on survival in T-DLBCL but not in in systemic DLBCL.

In order to further characterize the differences in the TME between T- and systemic DLBCL, we used NanoString digital gene expression profiling to assess the expression of 770 immune response genes in 60 T-DLBCL and 84 systemic DLBCL samples. In addition, we used multiplex immunohistochemistry (mIHC) to characterize TILs, tumor-associated macrophages (TAMs), NK-cells, checkpoint molecules, cell proportions, and cell interactions in 80 T-DLBCLs and 192 systemic DLBCLs.

Unsupervised hierarchical clustering of the gene expression data revealed clusters of genes with differential expression between T- and systemic DLBCLs. In T-DLBCL, 11 HLA genes were downregulated and genes related to B-cell receptor (BCR) signaling upregulated compared to systemic DLBCL. All T-DLBCL patients that clustered among the patients with systemic DLBCL had high T-cell signature expression, and systemic DLBCL patients that clustered among patients with T-DLBCL had significantly higher Ki-67 expression (p=0.00085). Based on the mIHC data, we observed not only a significantly lower proportion of FoxP3+ Tregs altogether but also a higher proportion of T-bet+FoxP3+ double positive Tregs in T-DLBCL compared to systemic DLBCL, confirming our previous findings on the significant role of T-bet+FoxP3+ double positive Tregs in the T-DLBCL TME. We also observed less TAMs in T-DLBCL TME. Unsupervised hierarchical clustering of the cell interaction data verified that distinct interaction clusters are found and separate the patients into different subgroups. Interactions of cytotoxic T-cells were more commonly seen in T-DLBCL whereas interactions of PD-1 expressing cells and interactions between TILs and TAMs were more frequent in systemic DLBCL.

Taken together, our results reveal differences in the TME between T- and systemic DLBCL, and further emphasize the impact of immune escape and distinct immune cells in T-DLBCL. Future studies are ongoing in order to further characterize the cell-to-cell interactions, their association with survival, and TME differences between T- and systemic DLBCL, in particular non-GCB DLBCL.

Disclosures: Leppa: Bayer: Research Funding; Orion Pharma: Consultancy; Pfizer: Consultancy; Beigene: Consultancy; Genmab: Research Funding; BMS: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Nordic Nanovector: Research Funding.

*signifies non-member of ASH