TGF-β Signaling Blockade Necessary for Anti-HCC Activity Via NK Cells

Transforming growth factor beta (TGF-β) is a cytokine that is highly expressed in the liver tumor microenvironment and is prone to inhibiting immune cell activity, causing the proliferation of hepatocellular carcinoma (HCC).

Targeted therapies such as sorafenib are often not curative, and while immunotherapy paired with vascular endothelial growth factor inhibitors are considered first-line options, they only provide modest efficacy.

New research by Dan Kaufman, MD, PhD, and colleagues has utilized human induced pluripotent stem cells (iPSCs) to produce natural killer (NK) cells that can improve anti-HCC activity when used in combination with TGF-β activity inhibitors.

Previous studies have utilized chimeric antigen receptor (CAR)-expressing T cells or CAR-expressing NK cells against HCC, but clinical efficacy has been limited, and one study demonstrated significant toxicity.

The iPSC-NK cells were developed using knockout TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) paired with CARs that target either GPC3 or AFP.

NK cells can kill target cells through granule-dependent pathways using granzymes and perforins, or granule-independent induction of cell death via death-receptor pathways. Previous trials have demonstrated that primary NK cells iPSCs with or without CAR expression are relatively safe and do not cause any significant toxicities such as cytokine-release syndrome, neurotoxicity, or graft-versus-host disease.

The researchers hypothesized that altering iPSC-derived NK cells to overcome TGF-β-mediated inhibition combined with expression of anti-HCC CARs would improve their anti-tumor activity. iPSC-derived NK cells were developed to overcome TGF-β inhibition and then incorporated an anti-GPC3 or anti-AFP CAR to induce specific tumor killing. The altered NK cells that were resistant to TGF-β inhibition were found to demonstrate significantly improved anti-tumor activity.

While the TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and can improve anti-HCC activity, the expression of anti-HCC CARs on iPSC-NK cells did not result in effective anti-HCC activity unless there was also inhibition of TGF-β activity.

These results point to the importance of a TGF-β signaling blockade for effective NK cell function against HCC and possible other malignancies that express high levels of TGF-β.