Yin Zhao

Acute myeloid leukemia (AML) is characterized by significant immunosuppression, limiting the efficacy of immunotherapy. Monocytic AML presents unique immunosuppressive features and constitutes a challenging subtype, necessitating focused investigation. Using single-cell multiomic analyses of primary AML samples, we revealed the immunosuppression landscape of monocytic AML and identified biliverdin reductase B (BLVRB) as a marker of immunosuppressive monocytic AML cells. BLVRB depletion downregulated immunomodulatory gene expression and sensitized AML cells to T-cell cytotoxicity, resulting in improved therapeutic efficacy in cell line–derived xenograft (CDX) and patient-derived xenograft (PDX) models. Mechanistically, BLVRB signals through the transcription factor MAFB to promote the expression of various immunosuppression-associated genes, resulting in inhibitory effects against anti-AML T cells. We further demonstrated that the small-molecule tamibarotene targets BLVRB, enhancing the efficacy of both chimeric antigen receptor (CAR) T and anti–PD-1 antibody therapies in AML. These findings elucidate the critical mechanism regulating immunosuppression in monocytic AML and identify BLVRB as a therapeutic target for improving AML immunotherapy. Significance: We revealed the particularly immunosuppressive feature of the monocytic AML subset and identified BLVRB-targeting strategies to reverse AML immunosuppression. Genetic disruption or pharmacologic inhibition of BLVRB sensitized AML cells to T cell–mediated cytotoxicity, offering potential strategies to enhance the therapeutic potency of immunotherapy against AML.

Dysregulation of RNA N ⁶ -methyladenosine (m ⁶ A) readers has been linked to various diseases, but the therapeutic potential of small-molecule inhibitors targeting them is of interest. Here, we reported the identification and characterization of a potent and selective first-in-class inhibitor (YL-5092) of YTHDC1, a nuclear RNA m ⁶ A reader. We provided a high-resolution cocrystal structure of the YTHDC1–YL-5092 complex. In acute myeloid leukemia (AML) models, YL-5092 blocked the binding of YTHDC1 to its m ⁶ A substrates and reduced mRNA stability, resulting in apoptosis of AML cells and myeloid differentiation. In multiple xenograft models of AML representing disease heterogeneity, YL-5092 alone or in combination with standard AML therapy eliminated leukemia and extended survival. Moreover, YL-5092 functionally impaired leukemia stem cells yet spared normal hematopoietic counterparts. Collectively, our work demonstrates the efficacy of a selective YTHDC1 inhibitor and suggests that targeting of m ⁶ A readers is a potential strategy in the treatment of hematologic cancers.

Foot-and-mouth disease (FMD) is characterized by a pronounced lymphopenia that is associated with immune suppression. However, the mechanisms leading to lymphopenia remain unclear. In this study, the number of total CD4⁺, CD8⁺ T cells, B cells, and NK cells in the peripheral blood were dramatically reduced in C57BL/6 mice infected with foot-and-mouth disease virus (FMDV) serotype O, and it was noted that mice with severe clinical symptoms had expressively lower lymphocyte counts than mice with mild or without clinical symptoms, indicating that lymphopenia was associated with disease severity. A further analysis revealed that lymphocyte apoptosis and trafficking occurred after FMDV infection. In addition, coinhibitory molecules were upregulated in the expression of CD4⁺ and CD8⁺ T cells from FMDV-infected mice, including CTLA-4, LAG-3, 2B4, and TIGIT. Interestingly, the elevated IL-10 in the serum was correlated with the appearance of lymphopenia during FMDV infection but not IL-6, IL-2, IL-17, IL-18, IL-1β, TNF-α, IFN-α/β, TGF-β, and CXCL1. Knocking out IL-10 (IL-10^-/-) mice or blocking IL-10/IL-10R signaling in vivo was able to prevent lymphopenia via downregulating apoptosis, trafficking, and the coinhibitory expression of lymphocytes in the peripheral blood, which contribute to enhance the survival of mice infected with FMDV. Our findings support that blocking IL-10/IL-10R signaling may represent a novel therapeutic approach for FMD.