A new target for cancer immunotherapy
Much progress and excitement have recently focused on cancer immunotherapy, which takes advantage of the immune system’s ability to fight cancer. Immune cells called CD8 T cells play a major role in fighting cancer via their ability to infiltrate tumors and kill cancer cells. Over time, however, these T-cells lose their fervor and become exhausted, allowing cancer cells to gain the upper hand. Therefore, much scientific effort currently focuses on a better understanding of this exhaustion mechanism and on ways to reverse it in order to sustain CD8 T cell tumor-killing functions and promote tumor elimination by the immune system.
We recently observed that exhausted CD8 T cells residing in experimental mouse tumors express higher levels of an enzyme called protein kinase C (PKC)-eta compared to fully functional CD8 T cells. This finding suggests that PKC-eta is directly involved in the loss of CD8 T cell function and that its inhibition could restore an efficient anti-tumor CD8 T cell response leading to tumor rejection. Similar findings have been reported by others in CD8 T cells infiltrating human melanoma and liver cancer clinical samples, indicating a direct translational potential for this study. We therefore propose to analyze in detail the role of PKC-eta in CD8 T cell function and exhaustion and to investigate the impact of neutralizing this enzyme as a novel immunotherapeutic strategy for cancer. We will address these questions using human CD8 T cells and genetically altered mouse strains in which PKC-eta can be specifically deleted in different defined cell types (including CD8 T cells), thus mimicking the use of—yet to be developed—drugs that selectively inhibit the activity of PKC-eta.
We expect this study to shed light on the role of PKC-eta in CD8 T cell responses against tumors, and thus provide an important proof of concept that neutralizing PKC-eta can improve the immune response against tumors. The proposed studies will open avenues for further studies of the mechanisms at play, and will establish PKC-eta as a potential target for cancer immunotherapy. Better understanding of the underlying mechanisms could prompt the development of clinically useful inhibitors for the treatment of cancer patients.