Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma
Matias Autio, Suvi-Katri Leivonen, Oscar Brück, Satu Mustjoki, Judit Mészáros Jørgensen, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Harald Holte, Teijo Pellinen, Sirpa Leppä, Matias Autio, Suvi-Katri Leivonen, Oscar Brück, Satu Mustjoki, Judit Mészáros Jørgensen, Marja-Liisa Karjalainen-Lindsberg, Klaus Beiske, Harald Holte, Teijo Pellinen, Sirpa Leppä
Abstract
The tumor microenvironment (TME) and limited immune surveillance 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 cytolytic 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 clinically 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.)
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References
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