Nr4a1-loss causes an acceleration of Myc-driven lymphomagenesis and an induction of gene of the B7-CD28


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Alexander Deutsch1,Katrin Pansy1,Christine Beham-Schmid1,Andreas Prokesch1,Julia Feichtinger1
1Medical University of Graz, Graz, Austria

Abstract

Background

In aggressive lymphomas, low expression of NR4A1 is associated with poor cancer-specific survival and its overexpression suppresses lymphoma cell growth indicating its tumor suppressor properties.

Method

To comprehensively study the function of Nr4a1-loss in lymphomagenesis, we intercrossed the EµMyc lymphoma-mouse with the Nr4a1-/- mouse. Furthermore, we transplanted lymphoma cells of EµMyc-Nr4a1-/- and EµMyc-Nr4a1+/+ mice into immune-competent C57BL/6 mice and immune-deficient Fox-Chase-SCID beige mice. Finally, we determined the expression levels of the immune regulatory genes by RQ-PCR in our DLBCL patient cohort.

Results

Loss of Nr4a1 in the EµMyc lymphoma model significantly accelerated lymphomagenesis. RNA-Seq data revealed upregulation of immune regulator genes of the B7-CD28 family in EµMyc-Nr4a1-/- lymphomas. Transplanting lymphoma cells with or without Nr4a1-loss into immune-competent mice led to accelerated lymphoma-development and a decreased survival in the absence of Nr4a1 and to no differences in immune-incompetent mice, indicating that the loss of Nr4a1 results in a suppression of anti-lymphoma immune response. Gene expression analysis of primary and engrafted lymphomas revealed that Nr4a1 is specifically implicated in the regulation of Pd1-Pdl1-Pdl2 and Ctla4-CD80-CD86 axis. Furthermore, flow cytometry analyses demonstrated that tumors transplanted from EµMyc-Nr4a1-/- mice exhibited a significantly higher percentage of infiltrating T cells. Interestingly, the infiltrating CD8+ T cells displayed higher expressed Pd1 on their surface in transplanted tumors derived from EµMyc-Nr4a1-/- mice, whereas Ctla-4 has not been investigated so far. In the human setting, we detected a significant negative association of NR4A1 expression levels and the PD1- PDL1- PDL2- and CTLA4- CD80-CD86 in DLBCL confirming our mouse data.

Conclusion

Our data suggest that the tumor suppressive function of Nr4a1 is mediated by the regulation of Pd1-Pdl1-Pdl2 and Ctla4-Cd80-Cd86 axis in aggressive lymphomas. Thereby, it seems that Nr4a1 loss significantly contributes to the immune evasion of aggressive lymphomas and that it might act as a potential target for anti-lymphoma therapy.