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

Project Information

Tex-Mex

Grant agreement ID: 101030034

DOI

10.3030/101030034

Project terminated on 31 July 2022

EC signature date 13 March 2021

Start date 15 July 2021

End date 4 October 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 171 473,28

EU contribution

€ 171 473,28

Coordinated by

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Italy

Periodic Reporting for period 1 - 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.)

Reporting period: 2021-07-15 to 2023-07-14

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In the course of the project, I have developed an in vitro material model for the study of biomechanical contributions to the development of T cell exhaustion. Preliminary results demonstrate a possible influence of the stiffness of substrates on the development of exhaustion but additional work, through a collaboration, is under way to replicate and further characterise this effect.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Elucidating the biomechanical effect on T cell exhaustion is an important contribution to the field that could lead to the development of more targeted therapeutic strategies. Specifically, new synthetic biology approaches based on mechanical sensing could enable specifically counteracting exhaustion in the tumour microenvironment, minimising the risk of off target effects. For example, in the future, ultra-specific biomechanosensor-actuator devices could be engineered combining "mechanosensors" with biosensors to prevent the development of exhaustion in tissues with specific mechanical properties. This could thus improve the effectiveness of cell-based cancer therapeutics by improving the specificity of genetic devices.

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