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ALKBH5 Drives Immune Suppression Via Targeting AXIN2 to Promote Colorectal Cancer and Is a Target for Boosting

Jianning Zhai1, Huarong Chen2, Chi Chun Wong1

  • 1Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.

Gastroenterology
|May 11, 2023
PubMed
Abstract

Insights

Targeting ALKBH5, an RNA eraser, can enhance immune checkpoint blockade therapy in colorectal cancer (CRC). This study reveals an ALKBH5-driven axis that promotes tumor growth and immune suppression in CRC.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Immune checkpoint blockade (ICB) therapy benefits limited colorectal cancer (CRC) patients.
  • Identifying CRC-intrinsic factors that modulate ICB efficacy is crucial.
  • AlkB homolog 5 (ALKBH5) is an RNA N6-methyladenosine eraser implicated in CRC progression.

Purpose of the Study:

  • To investigate the role of ALKBH5 in CRC and its potential as a target to improve ICB therapy.
  • To elucidate the molecular mechanisms by which ALKBH5 influences the tumor immune microenvironment in CRC.

Main Methods:

  • Clinical significance of ALKBH5 assessed in 205 human CRC samples.
  • Functional studies conducted in allografts, CD34+ humanized mice, and intestine-specific Alkbh5 knockin mice.
  • RNA sequencing and methylated RNA immunoprecipitation sequencing used to identify ALKBH5 targets; nanoparticle-encapsulated ALKBH5-small interfering RNA developed for in vivo targeting.

Main Results:

  • High ALKBH5 expression correlates with poor CRC prognosis and promotes tumorigenesis by increasing myeloid-derived suppressor cells and decreasing natural killer and CD8+ T cells.
  • ALKBH5 targets AXIN2 mRNA, leading to its demethylation, dissociation from IGF2BP1, and degradation, resulting in Wnt/β-catenin hyperactivation.
  • ALKBH5 induces Dickkopf-related protein 1 (DKK1), which recruits myeloid-derived suppressor cells, driving immunosuppression; this effect is reversed by anti-DKK1.
  • ALKBH5 inhibition or anti-DKK1 therapy potentiates anti-PD1 efficacy in suppressing CRC growth by enhancing antitumor immunity.

Conclusions:

  • An ALKBH5-N6-methyladenosine-AXIN2-Wnt-DKK1 axis drives immune suppression and tumorigenesis in CRC.
  • Targeting ALKBH5 represents a promising strategy to sensitize CRC to immunotherapy.
Keywords:
Colorectal CancerDKK1MDSCsWnt/β-Catenin Signalingm(6)A Modification

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