| Project Detail |
Immunotherapy, particularly adoptive T cell therapies (ACT), has revolutionized cancer treatment, providing significant benefits to patients with haematological malignancies. Despite these successes, their effectiveness against solid tumors remains limited. A major unaddressed obstacle in treating solid malignancies with ACT is the suppression of T cells within the tumor microenvironment (TME), which hampers their sustained activity against tumor cells. Thus, there is a critical need to optimize these therapies to be effective against a wider range of cancer types. One promising approach involves engineering adoptive T cells with switch receptors (SRs) that convert the detection of extracellular suppressive signals into intracellular T cell activation. Damage-associated molecular patterns (DAMPs) are endogenous danger ligands and powerful innate immune agonists that signal through Toll-like receptors (TLRs) to various cell types, playing an essential role in mounting protective immunity. However, the potential to utilize these innate immune signals to empower therapeutic T cells remains unexplored. This research proposal aims to enhance ACT against solid tumors by leveraging innate immune signals to improve T cell function within the suppressive TME. Specifically, the goals are (1) to design innovative SRs that amplify TLR costimulatory signalling upon detecting TME immunosuppressive factors, and (2) to incorporate these SRs into T cells, evaluating their therapeutic potential in both TCR-T and CAR-T therapies using complementary murine and human tumor models. By harnessing innate inflammatory signals, the proposed strategy seeks to boost fitness, cytotoxicity, and resilience of infused T cells, enabling them to navigate and function more effectively within the immunosuppressive TME of solid tumors. The advancements from this research could be transformative for cancer treatment paradigms, offering new hope for a broader spectrum of cancer patients. |
