In patients with advanced disease, adoptive cancer immunotherapy can produce objective clinical effectiveness; nevertheless, a sustained response is only obtained in a small percentage of instances. The ability of injected T cells to remain is a critical predictor of a long-term therapeutic response. Antitumor T cells undergo genome-wide epigenetic architectural modification in response to recurrent antigen contacts, resulting in increasing T-cell differentiation and loss of lifespan. For a study, researchers discovered PR domain zinc finger protein 1 (PRDM1), also known as Blimp-1, as a critical epigenetic gene linked to final T-cell differentiation in the investigation. In repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells, genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion. In vivo, PRDM1 disruption encouraged the proliferation of less differentiated memory CAR-T cells, which boosted T-cell persistence and therapeutic effectiveness in a variety of tumor types.
Mechanistically, PRDM1-ablated T cells increased chromatin accessibility to the genes that drive memory formation, resulting in the acquisition of gene expression patterns resembling early memory T cells. PRDM1 deletion also allowed T-cell receptor-engineered T cells and tumor-infiltrating lymphocytes to preserve an early memory phenotype and cytokine polyfunctionality. In other words, targeting PRDM1 promoted the development of better antitumor T cells, which might be useful in a variety of cancer immunotherapies.
