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STAT5 and STAT3 balance shapes dendritic cell function and tumor immunity

ABSTRACT: Immune checkpoint blockade (ICB) has transformed cancer therapy. Therapeutic efficacy of ICB depends on dendritic cell (DC)-mediated tumor antigen presentation, T-cell priming and activation. However, the relationship between the key transcription factors in DCs and ICB efficacy remains unknown. Here, we discover that ICB reprogramed the interplay between the STAT3 and STAT5 transcriptional pathways in DCs, thereby activating T-cell immunity, and enabling ICB efficacy in cancer patients and tumor bearing mice. Mechanistically, STAT3 competed with STAT5 for JAK interaction, determining the fate of DC function. As STAT3 is often activated in the tumor microenvironment (TME), we designed specific PROTAC degraders of STAT3, SD-36 and SD-2301. Low doses of SD-36 selectively and preferentially degraded STAT3 in DCs and reprogramed the DC transcriptional network toward immunogenicity. Furthermore, SD-36 monotherapy efficiently treated mice bearing large, advanced tumors and ICB resistant tumors without any signs of toxicity. Notably, SD2301 exhibits superior therapeutic efficacy compared to SD-36. Thus, the crosstalk between STAT3 and STAT5 determines DC phenotype in the TME and STAT3-degradation holds promise for cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE289764 | GEO | 2025/05/14

REPOSITORIES: GEO

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Project description:Dendritic cells (DC) play a vital role in the induction of activation or tolerance of immune response. STAT3 is a master transcriptional regulator of immune response in DCs by positively or negatively regulating DC function, but the mechanisms are unknown. STAT3 is post-translationally modified by acetylation or phosphorylation. While much is understood about transcriptional targets of phosphorylated STAT3, the gene targets and the functional impact of acetylated-STAT3 remain unclear. We aimed to answer the gene targets of acetylated-STAT3 and test the hypothesis that acetylation of STAT3 plays a key role in negative regulation of DCs. We performed genome-wide binding analysis of acetyl-STAT3 by ChIP-Seq coupled with gene expression microarrays. Acetylation of STAT3 induced by SAHA increased its capability to bind to target DNA sites in genome. Theses binding sites were mostly proximal but some were also distal up to over 100 kb from transcription start site. Gene expression array showed 1701 genes up-regulated and 1668 genes down-regulated. Proximal binding of acety-STAT3 showed more effective transcription function than distal binding. In top 500 binding peaks, the frequency of canonical motifs bound by acetyl-STAT3 were significantly higher than that for noncanonical motifs (p<0.00001). Functional analysis revealed that acetyl-STAT3 regulates target genes by upregulating genes that are primarily involved in negative regulation of cytokine production and IL-10 signaling, or downregulating genes that are primarily involved in immune effector process and antigen processing/presentation. Upregulation of IL-10Ra by acetyl-STAT3 contributes to the enhanced sensitivity of IL-10 signaling and negative regulation of DC function. Bone marrow derived dendritic cells were treated with SAHA (500 nm) or diluent for 12 hours. ChIP was performed using antibodies against STAT3, H3K4me3 and matched IgG control. DNA binding profiles were generated by deep sequencing using Illumina HiSeq 2000.

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STAT5 and STAT3 balance shapes dendritic cell function and tumor immunity

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