Researchers at Duke University have advanced cancer T-cell therapy using CRISPR for high-throughput screening of human immune cells. They discovered BATF3, a master regulator transcription factor gene, which reprograms thousands of genes in T cells, enhancing their ability to destroy cancer cells. This breakthrough could amplify the efficacy of existing and developing T-cell therapies and extend their application to other diseases like autoimmune disorders.

Sean McCutcheon, co-lead author, notes that T cells often become ‘tired’ and lose their cancer-fighting ability. The team’s approach aims to strengthen T cells by mimicking successful naturally occurring cell states. The study, led by Charles Gersbach and reported in Nature Genetics, explores transcriptional and epigenetic regulators in human CD8+ T cells.

Adoptive T-cell therapy (ACT), a decade-old cancer treatment method, involves genetically engineered T cells targeting cancer cells. However, its effectiveness against solid tumors is limited due to physical barriers and T-cell exhaustion. Gersbach’s lab developed a CRISPR-Cas9 method to modulate genes without cutting them, focusing on the “dark genome” areas that change as T cells transition between states.

Their screening identified 120 master regulator genes affecting T-cell function. BATF3 emerged as a key gene, enhancing T cells’ potency and resistance to exhaustion. Tests showed that BATF3 overexpression in T cells led to their improved performance against human breast cancer tumors in a mouse model.

The methodology’s broader impact lies in its potential to identify and modulate master regulators, improving therapeutic performance. This approach allows profiling master regulators using various T cell sources or cancer models, representing a significant advancement in making T-cell therapy more effective for more patients and cancer types.

McCutcheon’s further studies on BATF3, involving CRISPR knockout screens of over 1,600 gene expression regulators, revealed new factors for enhancing T-cell therapy. This catalog of genes opens avenues for developing next-generation cancer immunotherapies, potentially enabling patient-specific or generalized T cells for a wide range of cancers.

McCutcheon, S.R., Swartz, A.M., Brown, M.C. et al. Transcriptional and epigenetic regulators of human CD8+ T cell function identified through orthogonal CRISPR screens. Nat Genet (2023).

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