Chemical inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

by Selleckchem | Aug 31 2023

Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune-related diseases including asthma and rheumatoid arthritis, treatment with small-molecule DNA-PKcs inhibitors decreased the disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection in a murine allogenic skin graft model. These in vivo studies suggest the use of DNA-PKcs inhibitors as immunotherapy for autoimmune and T cell-mediated disorders. In this study, we sought to characterize further the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that inhibition of DNA-PKcs using inhibitor NU7441 and the inhibitors currently in clinical trials for cancer therapy, M3184 and AZD7648, abrogated the activation of murine and human CD4+ and CD8+ T cells as evidenced by the reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and the proliferation of activated T cells. This reduced the ability of OTI-CD8+ T cells to kill cancer cells and the expression of IFNγ and cytotoxic genes. These results highlight a critical role for DNA-PKcs in T cells and validate future studies using DNA-PKcs inhibitors as immune modulation therapy for the treatment of immune-related diseases.

Comments:

The passage you provided highlights the potential of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) inhibitors as therapeutic targets for the modulation of T cell activity in various diseases, including autoimmune diseases, immune-related disorders, and cancer. The study mentioned aimed to further characterize the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential.

The researchers found that the inhibition of DNA-PKcs using different inhibitors, such as NU7441, M3184, and AZD7648, resulted in the suppression of activation in murine and human CD4+ and CD8+ T cells. This was evidenced by reduced expression of activation markers CD69 and CD25. Additionally, the inhibition of DNA-PKcs impaired metabolic pathways and hindered the proliferation of activated T cells.

Furthermore, the researchers observed that the inhibition of DNA-PKcs diminished the ability of activated OTI-CD8+ T cells to kill cancer cells. It also led to reduced expression of IFNγ (interferon-gamma) and cytotoxic genes, which are important for T cell-mediated anti-tumor responses.

These findings emphasize the critical role of DNA-PKcs in T cell function and validate the potential use of DNA-PKcs inhibitors as immunotherapy for immune-related diseases. By targeting DNA-PKcs, these inhibitors could modulate T cell activity and potentially alleviate the severity of autoimmune diseases, immune-related disorders, and even enhance anti-tumor immune responses in cancer therapy.

It's worth noting that the information you provided seems to be a passage from a scientific study or research article. If you have any specific questions or would like to know more about a particular aspect of this topic, feel free to ask.