Inhibition of T and NK cells function by oncobacteria

Natural killer (NK) and cytotoxic T lymphocytes (CTL) kill infected and malignant cells. The activity of T cells and NK cells is controlled by a balance of signals obtained from inhibitory and activating receptors. In general, inhibitory receptors carry ITIM motifs in their cytoplasmic tail, which inhibits immune cell activity. Thus, unleashing the inhibition (known as checkpoint) will result in enhanced immune cell function. Indeed, checkpoint tumor therapy has become one of the biggest advantages in fighting cancer. Certain types of bacteria, such as Fusobacterium nucleatum (F. nucleatum), are present in some tumors. Several studies have shown a correlation between intratumoral F. nucleatum levels and colorectal tumorigenesis. Furthermore, high F. nucleatum abundance in the tumor has been linked to more aggressive tumor behavior. Work from our laboratory showed that NK cell killing of various tumors is inhibited by the F. nucleatum protein Fap2. Fap2 can bind the human inhibitory receptor TIGIT that is expressed on many immune cells. The interaction between Fap2 of F. nucleatum and TIGIT, protects tumors from immune cell attack. In this research we investigate whether F. nucleatum and later additional oncobacteria, such as Helicobacter pylori, that are present in tumors interact with other inhibitory receptors of NK cells and T cells. To investigate this, we use a reporter system using transfected BW cells. The discovery of oncobacteria that interact with inhibitory receptors will enable the development of new drugs for cancer therapy that will target not only the inhibitory receptors but also the oncogenic bacteria.