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

• Published in: Cell reports (Cambridge) 2021-05, Vol.35 (5), p.109076-109076, Article 109076
• Main Authors: Vaena, Silvia, Chakraborty, Paramita, Lee, Han Gyul, Janneh, Alhaji H., Kassir, Mohamed Faisal, Beeson, Gyda, Hedley, Zachariah, Yalcinkaya, Ahmet, Sofi, M. Hanief, Li, Hong, Husby, Monica L., Stahelin, Robert V., Yu, Xue-Zhong, Mehrotra, Shikhar, Ogretmen, Besim
• Format: Article
• Language: English
• Subjects: Aging; Animals; Ceramides - metabolism; CerS6; Humans; immunotherapy; lipid signaling; melanoma; Mice; Mitochondria - metabolism; mitophagy; PKA; Signal Transduction; sphingolipids and ceramide; SS SphK2; T cell; T-Lymphocytes - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109076

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. [Display omitted] •CerS6-generated C14/C16 ceramide induces mitophagy in activated aging T cells•Aging-induced mitochondrial ceramide inhibits protein kinase A, leading to mitophagy•Aging and ceramide-dependent mitophagy attenuates the antitumor functions of T cells•Inhibiting ceramide-dependent mitophagy restores aging T cells’ antitumor activity Vaena et al. define the mechanism whereby aging-mediated induction of ceramide-dependent mitophagy ameliorates antitumor functions of T cells via the inhibition of PKA. The attenuation of ceramide metabolism or activation of PKA prevents mitophagy and restores the central memory phenotype in aging T cells, improving T cell-mediated immunotherapeutic control of tumor growth.