Grant: Operating Grant

An effective immune system is essential for limiting the emergence of cancers and for aiding in the recovery from cancer. It has recently been recognized that the failure of the immune surveillance system is primarily the result of defects in the antigen presentation machinery of certain malignant cells. The immune response detects abnormal peptides, or antigens, in the context of a multi-part molecule known as MHC I on the surface of cells, and this functions as an effective tumour detection system. However, many lung carcinomas exhibit a loss of MHC I on their surface and transporter of antigen processing (TAP) downregulation, as do other cancers such as breast, ovarian, prostate, and cervical cancer. Failure of this antigen presentation system allows malignant cells to grow and in some cases, to develop into metastatic cancers. Overall, 90% of carcinomas lack functional MHC I molecules. Thus, these tumour cells are hidden from the cellular arm of the immune system and grow into tumours that may eventually result in death. We show strong evidence of strategies to increase the recognition of cancers by the immune system will halt tumour growth and metastases. Key Research Aim: We have found that metastatic carcinomas lack positive regulators of the TAP-1 gene. We have thus cloned candidate regulators and plan to express these regulatory genes to confirm they can enhance immune recognition of cancer in tumour bearing animals.