Conditional Myeloid-Specific Inhibition of UBE2N Hinders YUMM1.7 Growth
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The role of UBE2N in myeloid cell-mediated immune suppression in cancer remains undefined. Here, we examined the function of UBE2N in myeloid cell-mediated tumor progression using a temporally inducible myeloid-specific knockout model ( LysM CreER Ube2n fl/fl ). Temporally induced deletion of Ube2n in myeloid cells ( Ube2n MyeKO ) significantly hindered growth of YUMM1.7 melanoma. This was accompanied by reduced myeloid cell burden within the tumor microenvironment. We observed altered abundance of PD-1, PD-L1, and SPP1 in the Ube2n MyeKO tumor microenvironment at the tissue level. In vitro analysis showed that knock-in expression of a catalytically deficient UBE2N C87S mutant in bone marrow-derived macrophages (BMDMs) markedly decreased expression of Spp1 . We observed decreased SPP1 secretion in Ube2n MyeKO BMDM-conditioned media (CM). Treatment with Ube2n MyeKO BMDM-CM decreased co-expression of PD-1, TIM-3, and LAG-3 on chronically stimulated T cells. Antibody-mediated neutralization of SPP1 in Ube2n WT BMDM-CM decreased PD-1 expression on CD8+ T cells. Together, these findings suggest a role for myeloid UBE2N in YUMM1.7 progression.
