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Published on: November 16, 2016
Gene expression meta-analysis reveals immune response convergence on the IFNγ-STAT1-IRF1 axis and adaptive immune
Matthew A Care1,2, David R Westhead2, Reuben M Tooze3
1Section of Experimental Haematology, Wellcome Trust Brenner Building, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.
Background:
Cancers 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.
Methods:
Using 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.
Results:
T-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.
Conclusion:
Immune responses in DLBCL converge onto the IFNγ-STAT1-IRF1 axis and link to diverse potential mediators of adaptive immune resistance identifying future therapeutic targets.
Insights
The immune response in diffuse large B-cell lymphoma (DLBCL) utilizes the IFNγ-STAT1-IRF1 pathway, influencing outcomes and identifying therapeutic targets for adaptive immune resistance.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Cancers evade immune surveillance through adaptive mechanisms.
- Immune responses in carcinoma and melanoma involve cytotoxic effectors and IFNγ-STAT1-IRF1 signaling.
- Local interferon-driven immune checkpoints can cause adaptive immune resistance.
Purpose of the Study:
- To investigate the host immune response in diffuse large B-cell lymphoma (DLBCL).
- To determine if immune polarization and adaptive resistance patterns seen in other cancers apply to DLBCL.
- To establish DLBCL as a model for understanding immune responses in lymphoid malignancies.
Main Methods:
- Analysis of ten publicly available gene expression datasets (2030 cases) of DLBCL.
- Classification of DLBCL based on "cell of origin" and identification of polarized immune response gene patterns.
- Development of a linear classifier for immune response gene expression, validated independently of "cell of origin" classification.
Main Results:
- A defining feature of DLBCL immune response is T-cell and cytotoxic gene expression polarized along the IFNγ-STAT1-IRF1 axis.
- This immune response correlates with improved patient outcomes, especially in germinal center B-cell DLBCL.
- Gene expression analysis revealed a hierarchy of immune-regulatory genes, with IDO1, LAG3, and FGL2 preceding PD1-ligands (CD274, PDCD1LG2).
Conclusions:
- Immune responses in DLBCL are characterized by convergence on the IFNγ-STAT1-IRF1 axis.
- This pathway is linked to various mediators of adaptive immune resistance.
- The findings identify potential future therapeutic targets for DLBCL treatment.
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