New technology for inhibiting T cell exhaustion and reinvigorating exhausted T cells, which is essential for immune cell therapy of solid cancer

Professor Rho Hyun Seong and researcher Jinwoo Na of Seoul National University’s School of Life Sciences/Institute of Molecular Biology and Genetics released the online edition of ‘Science Advances’ (Sister magazine of ‘Science’) on NOV 25 after identifying genes that can 1) suppress the exhaustion process of CD8 T cells in cancer tissues, 2) stimulate to differentiate in to transient effector Cells with increased ability to kill cancer cells, and 3) reinvigorate previously exhausted CD8 T cells.

Professor Seong and researcher Na first demonstrated that Klf4 works as a key factor in regulating CD8 T cell activity within cancer tissue, and Klf4 effectively removes cancer cells without exhaustion from cancer tissue (see Figure 1). Their research showed CD8 T cells expressing Klf4 increased and multiplied, and significantly increased the secretion of cytotoxic substances that are essential for cancer cell removal, while CD8 T cells lacking Klf4 decreased cytotoxic secretions and showed decreased cell proliferation. Additionally, when Klf4 was induced in CD8 T cells that had already been exhausted within cancer tissue, it was confirmed that these cells were reinvigorated. Their cell-killing functions were reactivated. This is a groundbreaking result, reversing what had previously been viewed to be impossible for exhausted cells. By altering the genes, the researchers were able to recover and rehabilitate the original function of the T cells. Additionally, they found that clinically, the higher the Klf4 expression in actual cancer patients, the better their survival prognosis, and the higher the Klf4 expression, the greater the treatment effect of immune checkpoint inhibitors (see Figure 2).

This study marks a turning point in the development of immune cell therapy, proving that Klf4 is essential for CD8 T cells that penetrate cancer tissue to maintain high activity. Most CD8 T cells suffer exhaustion, and lose function. It is expected that immune cell therapies for solid cancers such as TIL, CAR-T, and PBL-T technology, will now be developed with this key platform technology to overcome T cell exhaustion.

This study was conducted with the support of the Ministry of Science and ICT (South Korea), and MedGene Therapeutics, Inc., a bio venture company that develops immune cell therapy technology (USA).