Tex-Mex · A synthetic biology approach to engineering exhaustion-free T cell therapies. Uncovering and counteracting biomechanical triggers of T cell dysfunction in the tumour microenvironment.

A synthetic biology approach to engineering exhaustion-free T cell therapies. Uncovering and counteracting biomechanical triggers of T cell dysfunction in the tumour microenvironment.

Cancer is the second leading cause of death in the EU, accounting for 1.4 million deaths and 3 million new cases in 2018, with an estimated healthcare cost of €130 billion each year. Cancer is also one of the five priority mission areas of Horizon Europe 2021-2027. Chimeric antigen receptor (CAR) T cell therapy is a ground-breaking cancer treatment that has demonstrated striking results in fighting blood cancers. However, T cell exhaustion, a process that results in the progressive development of lymphocyte dysfunction due to prolonged antigen stimulation in cancer, chronic inflammation or infection, has been a major obstacle in translating CAR T cell treatments to solid tumours. Inflamed organs and solid tumour growth result in microenvironments for T cells that are not only biochemically, but also biomechanically distinct from physiologic conditions. Notably, the tumour microenvironment is characterized by increased stiffness, which is thought to correlate with malignancy, and high interstitial pressures. While biochemical pathways for exhaustion have received a lot of attention, potential biomechanical effects of the tumour microenvironment on T cell dysfunction are understudied. Biomechanical cues such as stiffness are widely understood to have an effect in the process of T cell activation, mediated by the mechanosensitivity of the T cell receptor (TCR), suggesting that long-term biomechanical effects on the development of T cell exhaustion are plausible. This Marie Sklodowska-Curie Actions project strives to elucidate the interplay between T cell exhaustion and the tumor biomechanical environment.

Data: CORDIS, © European Union