Verbesserungen der antitumoralen CD8+ T Zellfunktion durch die Inhibierung von CD36
Zusammenfassung der Projektergebnisse
My group identified a protein molecule, CD36, which inhibits protective immune responses in tumor. Metabolic fitness of T cells plays a pivotal role in regulating T cell-mediated immunity, and metabolic deregulation causes T cell exhaustion in chronic viral infection and cancer. The scavenger receptor CD36 limited lipid peroxidation by anti-tumor T cell-dependent immune responses. T cells adapted to alter lipid homeostasis in the tumor microenvironment by enhancing uptake and accumulation of lipids and lipid peroxidation in murine tumors. Functionally exhausted CD8+ TILs substantially increased CD36 expression, which positively correlated with lipid uptake and storage levels. In murine melanoma models, CD36-deficient T cells had considerably more robust anti-tumor activity and cytokine production than wild-type cells. These findings suggest that CD36 promotes the uptake of oxidized low-density lipoproteins (oxLDL) and induces lipid peroxidation in T cells, and oxLDL inhibits T cell functions in a CD36-dependent manner. Glutathione peroxidase 4 over-expression lowers lipid peroxidation and restores functionalities in T cells. These results suggest a critical role for the oxLDL-CD36 axis in promoting intratumoral T cell dysfunction and reveal CD36 as an immune checkpoint molecule in cancer.
Projektbezogene Publikationen (Auswahl)
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Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity, 54(7), 1561-1577.e7.
Xu, Shihao; Chaudhary, Omkar; Rodríguez-Morales, Patricia; Sun, Xiaoli; Chen, Dan; Zappasodi, Roberta; Xu, Ziyan; Pinto, Antonio F.M.; Williams, April; Schulze, Isabell; Farsakoglu, Yagmur; Varanasi, Siva Karthik; Low, Jun Siong; Tang, Wenxi; Wang, Haiping; McDonald, Bryan; Tripple, Victoria; Downes, Michael; Evans, Ronald M. ... & Kaech, Susan M.
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CD8 agonism functionally activates memory T cells and enhances antitumor immunity. International Journal of Cancer, 151(5), 797-808.
Madi, Alaa; Weisshaar, Nina; Buettner, Michael; Poschet, Gernot; Ma, Sicong; Wu, Jingxia; Mieg, Alessa; Hering, Marvin; Ming, Yanan; Mohr, Kerstin; ten Bosch, Nora & Cui, Guoliang
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Rgs16 promotes antitumor CD8 + T cell exhaustion. Science Immunology, 7(71).
Weisshaar, Nina; Wu, Jingxia; Ming, Yanan; Madi, Alaa; Hotz-Wagenblatt, Agnes; Ma, Sicong; Mieg, Alessa; Hering, Marvin; Zettl, Ferdinand; Mohr, Kerstin; Schlimbach, Tilo; Ten Bosch Nora; Hertel, Franziska; Müller, Lisann; Byren, Hannah; Wang, Mona; Borgers, Helena; Munz, Mareike; Schmitt, Lukas ... & Cui, Guoliang
