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

Author:

Hesterberg Rebecca S.12ORCID,Beatty Matthew S.1,Han Ying13,Fernandez Mario R.4ORCID,Akuffo Afua A.12,Goodheart William E.1,Yang Chunying4,Chang Shiun12,Colin Christelle M.1,Alontaga Aileen Y.1,McDaniel Jessica M.1,Mailloux Adam W.1,Billington Julia M. R.12ORCID,Yue Lanzhu15ORCID,Russell Shonagh26ORCID,Gillies Robert J.6ORCID,Yun Sang Y.7,Ayaz Muhammad7,Lawrence Nicholas J.8ORCID,Lawrence Harshani R.7ORCID,Yu Xue-Zhong9,Fu Jianing9ORCID,Darville Lancia N.10,Koomen John M.1011ORCID,Ren Xiubao3,Messina Jane12ORCID,Jiang Kun12ORCID,Garrett Timothy J.13ORCID,Rajadhyaksha Anjali M.1415,Cleveland John L.4,Epling-Burnette Pearlie K.1

Affiliation:

1. Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL;

2. Cancer Biology PhD Program, University of South Florida, Tampa, FL;

3. Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China;

4. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL;

5. Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China;

6. Department of Cancer Physiology,

7. Chemical Biology Core, and

8. Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL;

9. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC;

10. Proteomics and Metabolomics Core,

11. Department of Molecular Oncology, and

12. Department of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL;

13. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL; and

14. Pediatric Neurology, Pediatrics, Weill Family Brain and Mind Research Institute, and

15. Graduate Program in Neuroscience, Weill Cornell Medical College, Cornell University, Cornell, NY

Abstract

Abstract 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 CK1α, 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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