Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity
A partir de l'analyse du cholestérol du microenvironnement tumoral, cette étude met en évidence un mécanisme par lequel l'oxystérol, via l'altération des voies de signalisation du récepteur LXR et de la protéine SREBP2, favorise l'épuisement ou le dysfonctionnement des lymphocytes T en induisant un déficit de cholestérol dans ces cellules
The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXR? depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.
Cancer Cell , résumé, 2022