Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

Xu, S.; Chaudhary, O.; Rodriguez-Morales, P.; Sun, X.; Zappasodi, R.; Xu, Z.; Pinto, A. F. M.; Williams, A.; Chen, D.; Low, J. S.; Farsakoglu, Y.; Tang, W.; Wang, H.; Varanasi, S. K.; McDonald, B.; Tripple, V.; Downes, M.; Evans, R. M.; Abumrad, N. A.; Merghoub, T.; Wolchok, J. D.; Shokhirev, M. N.; Ho, P.-C.; Witztum, J. L.; Emu, B.; Cui, G.; Kaech, S. M.

doi:10.1101/2020.09.03.281691

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bioRxiv · 10.1101/2020.09.03.281691

Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses

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Abstract

T 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.

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Xu, S., Chaudhary, O., Rodriguez-Morales, P., Sun, X., Zappasodi, R., Xu, Z., Pinto, A. F. M., Williams, A., Chen, D., Low, J. S., Farsakoglu, Y., Tang, W., Wang, H., Varanasi, S. K., McDonald, B., Tripple, V., Downes, M., Evans, R. M., Abumrad, N. A., Merghoub, T., Wolchok, J. D., Shokhirev, M. N., Ho, P.-C., Witztum, J. L., Emu, B., Cui, G., Kaech, S. M.. 2020-09-04. Oxidized Lipids and CD36-Mediated Lipid Peroxidation in CD8 T Cells Suppress Anti-Tumor Immune Responses. https://doi.org/10.1101/2020.09.03.281691

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