Deletion of Cbl-b inhibits CAR T-cell exhaustion

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Kumar J, Kumar R, Singh AK, et al. Deletion of Cbl-b Inhibits CD8+ T-Cell Exhaustion and Promotes CAR T-Cell Function. Journal for ImmunoTherapy of Cancer. 2021; 9 (1) (doi: 10.1136/jitc-2020-001688).

Scientists must take a closer look at Cbl-b if they want to improve chimeric antigen receptor (CAR) T-cell therapies for solid tumors, which are promising but currently less than optimal in terms of efficacy. The primary shortcoming involves exhaustion of the effector CD8+ T cells that promote anti-tumor immunity. In the tumor microenvironment, they become exhausted and weaken. Using RNA-sequencing data, researchers discovered that Cbl-b, an E3 ubiquitin ligase enzyme, is upregulated in exhausted CD8+ tumor-infiltrating lymphocytes (TILs) and is implicated in the dysfunction of tumor-reactive TILs. They also found that inhibiting Cbl-b rescues CD8+ TILs from exhaustion and restores their effector function. Similarly, deletion of Cbl-b in CAR T cells prevents exhaustion and promotes CAR T-cell function. Together, the findings suggest that targeting the E3 ubiquitin ligase enzyme Cbl-b could help boost tumor cell killing in CAR T-cell therapies for solid tumors.

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Tags: Inhibitors, cells, CAR T, Exhaustion, Deletion, CBI-B