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HMGA1 promotes esophageal cancer progression by inhibiting STING-mediated anti-tumor immunity

ABSTRACT: HMGA1 promotes esophageal cancer progression by inhibiting STING-mediated anti-tumor immunity

PROVIDER: PRJNA1097547 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28592101_1.fastq.gz	Fastqsanger.gz
	SRR28592101_2.fastq.gz	Fastqsanger.gz
	SRR28592102_1.fastq.gz	Fastqsanger.gz
	SRR28592102_2.fastq.gz	Fastqsanger.gz
	SRR28592103_1.fastq.gz	Fastqsanger.gz

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Project description:Esophageal cancer (ESCA) is one of the most common gastrointestinal malignancies. Recently, immunotherapy has been successfully applied for cancer treatment. However, the overall response rate of immunotherapy in ESCA patients is low and most patients may develop drug resistance. High mobility group A1 (HMGA1) is a chromatin remodeling protein, which participates in the regulation of a variety of biological processes and promotes tumor progression. The role of HMGA1 in anti-tumor immunity, especially that in esophageal squamous cell carcinoma (ESCC), remains largely unknown. Herein, we demonstrate that HMGA1 inhibited the expression of the stimulator of interferon genes (STING), inactivated the secretion of type I IFNs (T1IFNs), downregulated interferon stimulating genes (ISGs), and suppressed the recruitment of tumor infiltrating lymphocytes (TILs) that improve anti-tumor immunity. Mechanistically, we further characterized that HMGA1 decreased the transcription of STING by competing with the transcription coactivator CBP/p300 to bind to cAMP response element binding protein (CREB). Knockdown of HMGA1 promoted the expression of STING, activated IRF3 signaling downstream of TBK1, and hence enhanced the production of T1IFNs. We further demonstrated that the role of HMGA1 in anti-tumor immunity was mediated by STING with orthotopic esophageal carcinoma models in Hmga1flox/floxK14 conditional knock-out, Sting knock-out (Sting-/-), and Hmga1flox/floxK14Sting-/- double knock-out mice. ESCC developed in Hmga1flox/floxK14 conditional knock-out mice possessed widely distributed TILs and were sensitive to STING agonists. In contrast, ESCC generated in Hmga1KI/KIK14 gene knock-in mice or Hmga1flox/floxK14Sting-/- were mostly “cold tumors” with much less TILs and were insensitive to STING agonists. Further, analysis of ESCC tissues from patients confirmed the negative correlation between HMGA1 expression and STING and T lymphocyte infiltration. Moreover, based on the binding pocket of HMGA1, we designed and synthesized a series of HMGA1 inhibitors and characterized that a perylene based nanoparticle PDIC-DPC bore a strong inhibitory effect on HMGA1 and promotes T lymphocyte infiltration. Together, we conclude that oncogenic HMGA1 promotes the tumorigenesis of ESCC by inhibiting STING-mediated antitumor immune. Targeting HMGA1 provides a new strategy for immunotherapy of esophageal cancer.

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HMGA1 promotes esophageal cancer progression by inhibiting STING-mediated anti-tumor immunity

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