Genomic DNA at Programmed cell death 1, Beta-2-microglobulin, and Fas cell surface death receptor loci (gDNA (PDCD1/B2M/FAS))

Genomic DNA at the PDCD1, B2M, and FAS loci serves as a multiplexed target for site-specific nucleases in the production of engineered T-cell therapies (Stadtmauer et al., 2020, Science). The PDCD1 locus encodes Programmed Cell Death 1 (PD-1), an inhibitory receptor that limits T-cell activity; its disruption prevents exhaustion and enhances anti-tumor potency (UniProt Q15116). The B2M locus encodes Beta-2-Microglobulin, essential for the assembly of MHC class I molecules; knocking out this gene allows for the creation of allogeneic, 'off-the-shelf' CAR-T cells by reducing host-mediated rejection (Ren et al., 2017, Clin Cancer Res). The FAS (CD95) locus encodes a death receptor that mediates apoptosis; its deletion protects therapeutic cells from Fas-ligand-induced death within the immunosuppressive tumor microenvironment (UniProt P25445). These genomic sites are typically targeted using CRISPR-Cas9, TALENs, or zinc finger nucleases to achieve permanent gene knockout (Jung et al., 2018, ACS Synth Biol). This strategy is a cornerstone of next-generation adoptive immunotherapy, aiming to improve the persistence and safety of cellular products in treating both liquid and solid tumors (PubMed PMC7471464).

Other names

PDCD1 locusB2M locusFAS locusCD95 locusProgrammed cell death 1 geneBeta-2-microglobulin geneFas cell surface death receptor geneMultiplexed gene editing sites

Targeted genomic disruption via site-specific nucleases (e.g., CRISPR-Cas9) to induce double-strand breaks followed by error-prone non-homologous end joining (NHEJ), resulting in gene knockout to eliminate inhibitory protein expression or reduce immunogenicity.