Targeting the TCR signaling checkpoint: A therapeutic strategy to reactivate memory T cells in the tumor microenvironment

Background: One of the major conundrums in cancer immunotherapy is why human tumors are not rejected, and progress despite the presence of inflammatory leukocytes in the tumor microenvironment. While studies addressing the mechanisms responsible for the failure of immunocompetent cells to control tumor progression have shed considerable light upon this issue, not enough is known about the mechanisms contributing to the regulation of tumor-associated T cells in the microenvironment of human tumors. Objective: A persistent and robust response is likely to be required for the complete eradication of tumors. Such a durable immune response will require the development and persistence of functional tumor-reactive memory T cells. Methods: Various studies have investigated the mechanisms of suppression in the tumor microenvironment. However, very few studies have investigated the hyporesponsiveness of tumor-associated T cells at the molecular level. This review focuses on the hyporesponsiveness of tumor-associated T cells and how this relates to the T cell receptor signaling cascade. Results/conclusions: We postulate that this hyporesponsiveness results from a normal regulatory mechanism or TCR signaling checkpoint that is initiated by the persistence of antigen. If the TCR checkpoint is defined, it will be possible to design therapeutic strategies that reverse the TCR arrest. Essentially, this will reactivate the T cells in situ, leading to the killing and lysis of tumors locally, the release of tumor antigens and the generation of a systemic antitumor immunity.