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Smyd5 mediates IL-4 epigenetic control of macrophage antigen presentation to drive cooperative T cell-mediated tumor suppression [RNA-Seq]

ABSTRACT: IL-4 is classically associated with “M2” macrophages considered tumor-immunosuppressive, yet marker-based labels poorly reflect macrophage function in tumors. Reports of a non-canonical, IL-4–imprinted macrophage state (M2inf) with trained-immunity features prompted us to test whether such imprinting contributes to antitumor immunity in vivo. Here we show that, in B16F10 melanoma, IL-4 programs macrophages through the lysine methyltransferase Smyd5 to deposit promoter-proximal H3K36me3, increase MHC class II, and potentiate T cell activation. Myeloid Il4ra deletion increased tumor burden and reduced MHC class II and intratumoral T cell activation, whereas co-transfer of IL-4–primed macrophages suppressed tumors and expanded activated CD4 and CD8 T cells. Antitumor benefit required adaptive lymphocytes and macrophage-intrinsic MHC class II, as Rag1 deficiency or macrophage Rfx5 deletion abrogated tumor suppression. These findings identify a non-canonical, IL-4–imprinted macrophage program that enables antigen presentation and cooperative T cell immunity in this tumor context.

ORGANISM(S): Mus musculus

PROVIDER: GSE315361 | GEO | 2026/01/26

REPOSITORIES: GEO

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Project description:Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described; whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets taking advantage from well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers: the combination of retinoic acid (RA) and interferon-alpha (IFN-a) and doxorubicin, and to non ICD inducers like gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells subjected to ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). In this sense, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for a proper immune system antitumor response activation. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression validated the inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and the inhibitory co-receptor LAG-3 on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of Class I and II MHC pathway, whose implication in ICD was demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.

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Smyd5 mediates IL-4 epigenetic control of macrophage antigen presentation to drive cooperative T cell-mediated tumor suppression [RNA-Seq]

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