A genome-scale screen for synthetic drivers of T cell proliferation.
Mateusz LegutZoran Z GajicMaria GuarinoZharko DaniloskiJahan A RahmanXinhe XueCongyi LuLu LuEleni P MimitouStephanie HaoTeresa DavoliCatherine DiefenbachPeter SmibertNeville E SanjanaPublished in: Nature (2022)
The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer 1 . However, further improvements are needed to increase response and cure rates. CRISPR-based loss-of-function screens have been limited to negative regulators of T cell functions 2-4 and raise safety concerns owing to the permanent modification of the genome. Here we identify positive regulators of T cell functions through overexpression of around 12,000 barcoded human open reading frames (ORFs). The top-ranked genes increased the proliferation and activation of primary human CD4 + and CD8 + T cells and their secretion of key cytokines such as interleukin-2 and interferon-γ. In addition, we developed the single-cell genomics method OverCITE-seq for high-throughput quantification of the transcriptome and surface antigens in ORF-engineered T cells. The top-ranked ORF-lymphotoxin-β receptor (LTBR)-is typically expressed in myeloid cells but absent in lymphocytes. When overexpressed in T cells, LTBR induced profound transcriptional and epigenomic remodelling, leading to increased T cell effector functions and resistance to exhaustion in chronic stimulation settings through constitutive activation of the canonical NF-κB pathway. LTBR and other highly ranked genes improved the antigen-specific responses of chimeric antigen receptor T cells and γδ T cells, highlighting their potential for future cancer-agnostic therapies 5 . Our results provide several strategies for improving next-generation T cell therapies by the induction of synthetic cell programmes.
Keyphrases
- single cell
- high throughput
- genome wide
- rna seq
- cell proliferation
- endothelial cells
- dendritic cells
- papillary thyroid
- cell therapy
- transcription factor
- dna methylation
- signaling pathway
- bone marrow
- induced apoptosis
- induced pluripotent stem cells
- high glucose
- gene expression
- pi k akt
- case report
- regulatory t cells
- cell cycle arrest
- childhood cancer
- minimally invasive
- crispr cas
- genome editing
- lymph node metastasis
- lps induced
- drug induced
- platelet rich plasma
- nk cells
- cell death
- mesenchymal stem cells
- genome wide identification
- peripheral blood
- immune response
- human health
- acute myeloid leukemia