Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Abstract

Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.

Single-cell transcriptome analysis profiles the expression features of TMEM173 in BM cells of high-risk B-cell acute lymphoblastic leukemia

“…In particular, TMEM173 is involved in pyroptosis, of which the canonical pathway depends on TMEM173-mediated GSDMD cleavage [ 51 , 52 ]. Inducing pyroptosis in tumor cells has been regarded as an effective strategy for reducing tumor burden [ 53 , 54 ]. For B-ALL, tumor burden mainly derives from the clonal expansion of malignant B cells [ 55 ].…”

Combining Cryo-Thermal Therapy with Anti-IL-6 Treatment Promoted the Maturation of MDSCs to Induce Long-Term Survival in a Mouse Model of Breast Cancer

“…4T1 cells were labeled with calcein-AM in advance. Splenic CD4 + T and CD8 + T cells isolated using CD4 + T Cell Positive Selection Kit (StemCell Technologies, Vancouver, BC, Canada) and CD8 + T Cell Isolation Kit (StemCell Technologies, Vancouver, BC, Canada) were plated in a 96-well plate, then co-cultured with 4T1 cells at ratio of 10:1 as reported by Mishra et al and Ning et al [ 60 , 61 ]. Cells were cultured in complete RPMI 1640 medium at 37 °C in a 5% CO 2 incubator for 6 hours.…”

Role of pyroptosis in the pathogenesis and treatment of diseases

“…It reveals a general function of tumor‐cell GSDMD‐induced pyroptosis in enhancing anticancer immunity. 254 …”

“…demonstrate that mixed‐lineage leukemia 4 ablation decreases the expression of DNA methytransferases and RNA‐induced silencing complex, which causes GSDMD‐dependent pyroptosis and transcriptional reactivation of double‐stranded RNA for strengthened immunotherapy in human lung cancer (H1299) cells. It reveals a general function of tumor‐cell GSDMD‐induced pyroptosis in enhancing anticancer immunity 254 …”