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Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

Liam Baird1, Masayuki Yamamoto1

  • 1Department of Biochemistry and Molecular Biology, Tohoku University, Tohoku Medical Megabank Organization, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, Sendai 980-8575, Japan.

Redox Biology
|October 15, 2023
PubMed

Insights

Activating mutations in the KEAP1-NRF2 pathway promote cancer growth and treatment resistance. NRF2 activation also impairs anti-cancer immunity by reducing immune cell engagement and creating an immunologically cold tumor microenvironment.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Activating mutations in the KEAP1-NRF2 pathway are common in human cancers, conferring cytoprotective advantages and treatment resistance.
  • NRF2-activated cancers exhibit resistance to both chemotherapy and immune checkpoint inhibitors, with the underlying mechanisms of immune resistance being unclear.

Purpose of the Study:

  • To investigate how aberrant Nuclear factor erythroid 2-related factor 2 (NRF2) activity impacts the anti-cancer immune response.
  • To elucidate the mechanisms by which NRF2 activation contributes to immune evasion in human cancers.

Main Methods:

  • Analysis of NRF2-activated human cancers.
  • Assessment of immune editing processes, including antigen presentation via MHC-I and NK cell activating ligand expression.
  • Evaluation of immune effector cell infiltration and engagement within the tumor microenvironment.

Main Results:

  • NRF2-activated cancer cells undergo significant immunoediting, facilitating immune escape.
  • Key immunoediting mechanisms include reduced MHC-I antigen presentation and decreased expression of NK cell activating ligands.
  • These changes collectively inhibit immune effector cell infiltration and engagement, leading to an immunologically cold tumor microenvironment.

Conclusions:

  • Aberrant NRF2 activation in cancer promotes immune evasion through reduced immunogenicity and impaired immune cell interactions.
  • The immunoediting process driven by NRF2 contributes to the development of an immunosuppressive tumor microenvironment, characteristic of NRF2-activated cancers.
Keywords:
Immune evasionImmune surveillanceImmunoeditingKEAP1NFE2L2NISPNRF2Oxidative stressStress response

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