Cytokine inducible SH2 containing protein (CISH) (CISH)

Cytokine inducible SH2 containing protein (CISH) is a member of the suppressor of cytokine signaling (SOCS) family that serves as a potent intracellular checkpoint in immune cells, including T cells and natural killer (NK) cells (UniProt Q9NSE2). It functions by binding to phosphorylated tyrosine residues on cytokine receptors, such as the IL-2 receptor, or Janus kinases (JAKs), which inhibits the JAK-STAT signaling pathway and specifically dampens STAT5 activation (PubMed: 26878114). In the context of cancer immunotherapy, CISH is often upregulated following T-cell receptor stimulation, leading to reduced effector function and contributing to immune cell exhaustion within the tumor microenvironment (PubMed: 25974303). Ex vivo CRISPR/Cas9 editing of the CISH gene is a therapeutic approach designed to knock out this negative regulator in adoptive cell therapies, such as CAR-T or CAR-NK cells. By removing this 'brake,' the edited immune cells exhibit enhanced metabolic fitness, increased proinflammatory cytokine production, and superior anti-tumor cytotoxicity against solid tumors (PubMed: 32544371). This strategy is currently being evaluated in clinical trials to improve the efficacy of cell-based medicines in oncology (ClinicalTrials.gov: NCT04629729).

Other names

CISSOCSG18B18CIS-1Suppressor of cytokine signaling

Gene knockout via CRISPR/Cas9 to permanently disrupt the CISH gene, preventing the expression of the CIS protein and thereby removing an intracellular 'brake' on cytokine signaling (specifically STAT5) to enhance immune cell potency.