Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity

被引：79

作者：

Chakraborty, Paramita ^{[1
]}

Vaena, Silvia G. ^{[2
]}

Thyagarajan, Krishnamurthy ^{[1
]}

Chatterjee, Shilpak ^{[1
]}

Al-Khami, Amir ^{[1
]}

Selvam, Shanmugam Panneer ^{[2
]}

Hung Nguyen ^{[3
]}

Kang, Inhong ^{[4
]}

Wyatt, Megan W. ^{[3
]}

Baliga, Uday ^{[4
]}

Hedley, Zachariah ^{[1
]}

Ngang, Rose N. ^{[2
]}

Guo, Beichu ^{[3
]}

Beeson, Gyda C. ^{[5
]}

Husain, Shahid ^{[6
]}

Paulos, Chrystal M. ^{[3
]}

Beeson, Craig C. ^{[5
]}

Zilliox, Michael J. ^{[7
]}

Hill, Elizabeth G. ^{[8
]}

Mehrotra, Meenal ^{[4
]}

Yu, Xue-Zhong ^{[3
]}

Ogretmen, Besim ^{[2
]}

Mehrotra, Shikhar ^{[1
]}

机构：

[1] Med Univ South Carolina, Dept Surg, Hollings Canc Ctr, Charleston, SC 29425 USA

[2] Med Univ South Carolina, Dept Biochem & Mol Biol, Hollings Canc Ctr, Charleston, SC 29425 USA

[3] Med Univ South Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA

[4] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA

[5] Med Univ South Carolina, Dept Pharmaceut & Biomed Sci, Charleston, SC 29425 USA

[6] Med Univ South Carolina, Dept Ophthalmol, Charleston, SC 29425 USA

[7] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA

[8] Med Univ South Carolina, Dept Publ Hlth, Hollings Canc Ctr, Charleston, SC 29425 USA

来源：

CELL REPORTS | 2019年 / 28卷 / 07期

关键词：

ACTIVATED RECEPTOR-GAMMA; PPAR-GAMMA; BIOACTIVE SPHINGOLIPIDS; TUMOR MICROENVIRONMENT; GROWTH; IMMUNOREGULATION; DIFFERENTIATION; ADIPOCYTES; EXPRESSION; LIPOLYSIS;

D O I：

10.1016/j.celrep.2019.07.044

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs. Mechanistically, we discovered a direct correlation between SphK1-generated S1P and lipid transcription factor PPAR gamma (peroxisome proliferator-activated receptor gamma) activity, which in turn regulates lipolysis in T cells. Genetic and pharmacologic inhibition of SphK1 improved metabolic fitness and anti-tumor activity of T cells against murine melanoma. Further, inhibition of SphK1 and PD1 together led to improved control of melanoma. Overall, these data highlight the clinical potential of limiting SphK1/S1P signaling for enhancing anti-tumor-adoptive T cell therapy.

引用

页码：1879 / +

页数：22

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