Low expression of ALOX15B modulates immunosuppressive tumor microenvironment in diffuse large-B cell lymphoma via the TAP1/MHC-I axis

The arachidonic acid (AA) metabolism is closely related to tumor immune evasion and chemo-resistance. ALOX15B (arachidonate 15-lipoxygenase type B), located on chromosome 17p, encodes a key enzyme in AA pathway. Interestingly, the expression of ALOX15B is independent of 17p status but is epigenetically regulated. Low ALOX15B expression predicts poor prognosis, with PGE2 activation and TAP1 suppression, reducing MHC-I expression and creating an immunosuppressive microenvironment. Tucidinostat, a histone deacetylase (HDAC) inhibitor, restores ALOX15B and enhances the TAP1/MHC-I axis, thus promoting lymphoma cell apoptosis, which correlates with the effect of tucidinostat plus immunochemotherapy in a phase II trial of patients with newly diagnosed DLBCL (NCT02753647). Our study provides insight into a novel therapeutic strategy to improve patient prognosis by epigenetically modulating lymphoma metabolism and optimizing the tumor microenvironment. Overall design: Bone marrow-derived B220+ B progenitor cells were transduced with retroviruses and then administered via tail-vein injection into C57BL/6 mice that had been sublethally irradiated (4.5 Gy, Cs137). All mice were randomly grouped before transplantation and were monitored twice a week until the start of treatment. Drug treatment was initiated 7 days after transplantation to ensure tumor engraftment in the shALOX15B group. The mice were randomly assigned to two groups: one group was treated with vehicle solution consisting of 0.2% carboxymethylcellulose saline and 0.1% Tween 80, while another group received tucidinostat at a dose of 12.5 mg/kg/day administered once daily via oral gavage. Pharmacological treatment was administered until tumors were observed in all subjects in the vehicle group. Single-cell RNA sequencing (scRNA-seq) was performed to analyze the transcriptional profiles of the tumor microenvironment or specific cell subpopulations.