Abstract
BackgroundCancers adapt to immune-surveillance through evasion. Immune responses against carcinoma and melanoma converge on cytotoxic effectors and IFNγ-STAT1-IRF1 signalling. Local IFN-driven immune checkpoint expression can mediate feedback inhibition and adaptive immune resistance. Whether such coupled immune polarization and adaptive resistance is generalisable to lymphoid malignancies is incompletely defined. The host response in diffuse large B-cell lymphoma (DLBCL), the commonest aggressive lymphoid malignancy, provides an empirical model.MethodsUsing ten publicly available gene expression data sets encompassing 2030 cases we explore the nature of host response in DLBCL. Starting from the “cell of origin” paradigm for DLBCL classification, we use the consistency of differential expression to define polarized patterns of immune response genes in DLBCL, and derive a linear classifier of immune response gene expression. We validate and extend the results in an approach independent of “cell of origin” classification based on gene expression correlations across all data sets.ResultsT-cell and cytotoxic gene expression with polarization along the IFNγ-STAT1-IRF1 axis provides a defining feature of the immune response in DLBCL. This response is associated with improved outcome, particularly in the germinal centre B-cell subsets of DLBCL. Analysis of gene correlations across all data sets, independent of “cell of origin” class, demonstrates a consistent association with a hierarchy of immune-regulatory gene expression that places IDO1, LAG3 and FGL2 ahead of PD1-ligands CD274 and PDCD1LG2.ConclusionImmune responses in DLBCL converge onto the IFNγ-STAT1-IRF1 axis and link to diverse potential mediators of adaptive immune resistance identifying future therapeutic targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0218-3) contains supplementary material, which is available to authorized users.
Highlights
We identified 127 genes associated with cell of origin (COO)-unclassified diffuse large B-cell lymphoma (DLBCL) relative to both activated B cell (ABC)- and germinal centre B cell (GCB)-DLBCL, while 209 genes were associated with both
COO-unclassified DLBCL is enriched for features of a polarized immune response To assess underlying biology in the COO-classified and COO-unclassified meta-profiles we developed an approach for integrated analysis of gene ontology (GO) and gene signature enrichment (Additional file 2) which applies hierarchical clustering to reciprocally assess the relationships of enriched ontology and signature terms and associated genes contributing to enrichments (Additional file 6)
In the context of gene expression profiling, morphologically defined T-cell and histiocyte-rich large B-cell lymphoma, which represents a relatively rare subcategory, has been characterized by evidence of an IFNassociated immune response, linked on the one hand with over-expression of PD1 (PDCD1) on infiltrating T cells when compared with classical Hodgkin lymphoma [52], or the expression of IDO1 when compared with nodular lymphocyte predominant Hodgkin lymphoma, another relatively rare lymphoma subtype [53]
Summary
The common association between cytotoxic responses and expression of IFN signatures and potential mediators of adaptive immune resistance has been further supported by analysis of solid tumour gene expression data from The Cancer Genome Atlas [9]. Such feedback may be mediated both at the immediate interface between tumour cell and cytotoxic lymphocyte, and by the establishment of a wider immune suppressive milieu in the tumour microenvironment
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