Abstract:

Lysis of tumor cells by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells is mediated by the ability of these cells to recognize classical, non-classical and MHC class I related molecules. My work has focused on understanding how tumor cells regulate the expression of these molecules and the effect that an anti-cancer modality, which is known to induce CTL and NK dependent anti-tumor immunity, has on the expression of these molecules. Stable cell surface expression of classical MHC class I molecules is dependent on their efficient assembly and loading. They bind peptides generated by proteasomal degradation of proteins in the cytosol, transported to the ER by TAP molecules and loaded onto immature classical MHC class I molecules through their interaction with tapasin. Tumor cells can evade CTL lysis by down-regulating the surface level of classical MHC class I molecules. We hypothesize that this is due in part to deficiencies in TAP and tapasin. TAP and tapasin play critical roles in the peptide loading of immature classical MHC class I molecules and their activities are co-regulated and intertwined making determination of their individual contributions to classical MHC class I expression difficult to unravel. We have characterized the first tapasin deficient human melanoma cell line and used it to demonstrate that tapasin limits the surface level of classical MHC class I molecules (even in the presence of undetectable TAP protein). Thus by down-regulating tapasin, tumors can evade immune recognition by CTLs. However, tumors that evade CTL lysis are often susceptible to NK lysis either via the recognition of stress inducible non-classical or MHC class I related molecules, or by the lack of surface bound classical MHC class I molecules, which provides an inhibitory signal to the NK cell. Non-classical and MHC class I related molecules are induced by several types of stress, such as infection, heat-shock and ROS among others. PDT is an anti-cancer modality that mediates its activity by the generation of ROS. Our laboratory has previously shown that PDT also activates NK and CTL-dependent anti-tumor immunity and that they are required in the long-term control of disease. We therefore hypothesized that PDT may affect the regulation of classical, non-classical and MHC class I related molecules in order to render tumors more immunogenic.