Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway

  • Leukemia. 2022 Jul;36(7):1907-1915. doi: 10.1038/s41375-022-01581-6.
M Hanief Sofi  #  1 ,  Linlu Tian  #  1  2 ,  Steven Schutt  1 ,  Imran Khan  3 ,  Hee-Jin Choi  1  2 ,  Yongxia Wu  1  2 ,  David Bastian  1 ,  Taylor Ticer  1 ,  Mohamed Faisal Kassir  4 ,  Firdevs Cansu Atilgan  4 ,  Jisun Kim  4 ,  Xiaohui Sui  1 ,  Aleksandra Zivkovic  5 ,  Shikhar Mehrotra  6 ,  John P O'Bryan  3 ,  Holger Stark  5 ,  Paul J Martin  7 ,  Besim Ogretmen  4 ,  Xue-Zhong Yu  8  9  10
Affiliations
  • 1. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
  • 2. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
  • 3. Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, USA.
  • 4. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
  • 5. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany.
  • 6. Department of Surgery, Medical University of South Carolina, Charleston, SC, USA.
  • 7. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 8. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA. [email protected].
  • 9. Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. [email protected].
  • 10. The Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. [email protected].
  • # Contributed equally.
PMID: 35513703 DOI: 10.1038/s41375-022-01581-6
Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for various hematologic malignancies, predominantly through potent graft-versus-leukemia (GVL) effect. However, the mortality after allo-HCT is because of relapse of primary malignancy and followed by graft-vs-host-disease (GVHD) as a major cause of transplant-related mortality. Hence, strategies to limit GVHD while preserving the GVL effect are highly desirable. Ceramide, which serves a central role in sphingolipid metabolism, is generated by ceramide synthases (CerS1-6). In this study, we found that genetic or pharmacologic targeting of CerS6 prevented and reversed chronic GVHD (cGVHD). Furthermore, specific inhibition of CerS6 with ST1072 significantly ameliorated acute GVHD (aGVHD) while preserving the GVL effect, which differed from FTY720 that attenuated aGVHD but impaired GVL activity. At the cellular level, blockade of CerS6 restrained donor T cells from migrating into GVHD target organs and preferentially reduced activation of donor CD4 T cells. At the molecular level, CerS6 was required for optimal TCR signaling, CD3/PKCθ co-localization, and subsequent N-Ras activation and ERK signaling, especially on CD4+ T cells. The current study provides rationale and means for targeting CerS6 to control GVHD and leukemia relapse, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.

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