Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 7, Issue 1, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41392-022-00915-1
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Funding
- National Natural Science Foundation of China [81830002, 82150108, 31991171, 32070951, 2021WWC04]
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Loss of NOXA, a BCL2 family protein, was identified as a key regulator of resistance to CAR T-cell therapy. Low NOXA expression was associated with worse survival in patients with B-cell lymphoma. In vitro and in vivo experiments showed that enhancing NOXA expression using HDAC inhibitors dramatically increased sensitivity of cancer cells to CAR T-cell clearance.
Despite the remarkable success of chimeric antigen receptor (CAR) T-cell therapy for treating hematologic malignancies, resistance and recurrence still occur, while the markers or mechanisms underlying this resistance remain poorly understood. Here, via an unbiased genome-wide CRISPR/Cas9 screening, we identified loss of NOXA, a B-cell lymphoma 2 (BCL2) family protein in B-cell malignancies, as a pivotal regulator of resistance to CAR T-cell therapy by impairing apoptosis of tumor cells both in vitro and in vivo. Notably, low NOXA expression in tumor samples was correlated with worse survival in a tandem CD19/20 CAR T clinical trial in relapsed/refractory B-cell lymphoma. In contrast, pharmacological augmentation of NOXA expression by histone deacetylase (HDAC) inhibitors dramatically sensitized cancer cells to CAR T cell-mediated clearance in vitro and in vivo. Our work revealed the essentiality of NOXA in resistance to CAR T-cell therapy and suggested NOXA as a predictive marker for response and survival in patients receiving CAR T-cell transfusions. Pharmacological targeting of NOXA might provide an innovative therapeutic strategy to enhance CAR T-cell therapy.
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