Deletion of Cbl-b inhibits CAR T-cell exhaustion

The following content was featured in a recent Abstracts newsletter distributed by ASTCT. The Abstracts newsletter highlights the latest research in the clinical research and translational science studies aspects of transplantation and cellular therapy. 

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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