4.7 Article

Cereblon harnesses Myc-dependent bioenergetics and activity of CD8(+) T lymphocytes

Journal

BLOOD
Volume 136, Issue 7, Pages 857-870

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019003257

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Funding

  1. National Natural Science Foundation of China [81702268]
  2. Natural Science Foundation of Tianjin [18JCYBJC93400]
  3. Celgene Corporation
  4. Cortner-Couch Endowed Chair for Cancer Research of the USF School of Medicine
  5. Lesa France Kennedy
  6. Leukemia and Lymphoma SocietySpecialized Center of Research (LLS-SCOR)
  7. National Institutes of Health, National Cancer Institute (NCI) Center Core Support grant [P30-CA076292]
  8. State of Florida
  9. NCI
  10. Moffitt Skin Cancer Specialized Programs of Research Excellence (SPORE) [P50CA168536]
  11. NCI Research Specialist award [R50CA211447]
  12. NCI National Research Service Award [F32CA203217]

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Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known neosubstrates, such as IKAROS, AIOLOS, and CK1 alpha, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8(+) T-cell effector responses. Specifically, Crbn deficiency in murine CD8(+) T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8(+) T cells. Notably, the metabolic control of CD8(+) T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8(+) T cells, and this phenotype can be exploited by treatment with drugs.

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