Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

Silvia Vaena; Paramita Chakraborty; Han Gyul Lee; Alhaji H Janneh; Mohamed Faisal Kassir; Gyda Beeson; Zachariah Hedley; Ahmet Yalcinkaya; M Hanief Sofi; Hong Li; Monica L Husby; Robert V Stahelin; Xue-Zhong Yu; Shikhar Mehrotra; Besim Ogretmen

doi:10.1016/j.celrep.2021.109076

Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response

Cell Rep. 2021 May 4;35(5):109076. doi: 10.1016/j.celrep.2021.109076.

Authors

Affiliations

¹ Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
² Department of Surgery, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
³ College of Pharmacy, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁴ Department of Microbiology and Immunology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁵ Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Department of Public Health, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA.
⁶ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
⁷ Departments of Biochemistry and Molecular Biology, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA. Electronic address: ogretmen@musc.edu.

Abstract

We lack a mechanistic understanding of aging-mediated changes in mitochondrial bioenergetics and lipid metabolism that affect T cell function. The bioactive sphingolipid ceramide, induced by aging stress, mediates mitophagy and cell death; however, the aging-related roles of ceramide metabolism in regulating T cell function remain unknown. Here, we show that activated T cells isolated from aging mice have elevated C14/C16 ceramide accumulation in mitochondria, generated by ceramide synthase 6, leading to mitophagy/mitochondrial dysfunction. Mechanistically, aging-dependent mitochondrial ceramide inhibits protein kinase A, leading to mitophagy in activated T cells. This aging/ceramide-dependent mitophagy attenuates the antitumor functions of T cells in vitro and in vivo. Also, inhibition of ceramide metabolism or PKA activation by genetic and pharmacologic means prevents mitophagy and restores the central memory phenotype in aging T cells. Thus, these studies help explain the mechanisms behind aging-related dysregulation of T cells' antitumor activity, which can be restored by inhibiting ceramide-dependent mitophagy.

Keywords: CerS6; PKA; SS SphK2; T cell; aging; immunotherapy; lipid signaling; melanoma; mitophagy; sphingolipids and ceramide.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging*
Animals
Ceramides / metabolism*
Humans
Mice
Mitochondria / metabolism*
Signal Transduction
T-Lymphocytes / metabolism*

Substances

Ceramides

Abstract

Publication types

MeSH terms

Substances

Grants and funding