| Autor: |
Michael Downes, Joseph L. Witztum, Nada A. Abumrad, Bryan McDonald, Antonio Pinto, Susan M. Kaech, Ping-Chih Ho, Maxim N. Shokhirev, Xiaoli Sun, Shihao Xu, Dan Chen, Taha Merghoub, Jun Siong Low, Patricia Rodríguez-Morales, Ronald M. Evans, Victoria Tripple, Brinda Emu, Haiping Wang, Yagmur Farsakoglu, Jedd D. Wolchok, Siva Karthik Varanasi, April Williams, Ziyan Xu, Omkar Chaudhary, Roberta Zappasodi, Wenxi Tang, Guoliang Cui |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.09.03.281691 |
| Popis: |
SummaryT cell metabolic fitness plays a pivotal role in anti-tumor immunity and metabolic deregulation causes T cell dysfunction (i.e., ‘exhaustion’) in cancer. We identify that the scavenger receptor CD36 limits anti-tumor CD8+T cell effector functions through lipid peroxidation. In murine tumors, oxidized phospholipids (OxPLs) were highly abundant and CD8+TILs increased uptake and accumulation of lipids and lipid peroxidation. Functionally ‘exhausted’ CD8+TILs substantially increased CD36 expression and CD36-deficient CD8+TILs had more robust anti-tumor activity and cytokine production than wild-type cells. We further show that CD36 promotes uptake of oxidized low-density lipoproteins (OxLDL) and induces lipid peroxidation in CD8+TILs, and OxLDL inhibits CD8+T cell functions in a CD36-dependent manner. Moreover, glutathione peroxidase 4 (GPX4) over-expression lowers lipid peroxidation and restores functionalities in CD8+TILs. These results define a key role for an oxidized lipid-CD36 axis in promoting intratumoral CD8+T cell dysfunction. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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