A computational investigation of pathways for ex vivo differentiation and dysfunction of healthy and patient T cells

Cancer alters T cell differentiation kinetics rather than the structure of the differentiation pathway during short-term ex vivo expansion, as supported by model fits to healthy and patient data.

• Why it matters: Limiting differentiation into exhaustion-associated phenotypes is a key challenge in adoptive T cell therapy, and biological literature uncertainty motivates model-informed hypothesis testing.
• What they did: The study constructs thousands of phenotype-to-phenotype pathways from literature, formulates ordinary differential equation models, fits them to ex vivo expansion data from healthy individuals and cancer patients, and accepts the closest-fitting models.
• The result: Accepted models suggest T cells do not differentiate unidirectionally ex vivo and instead dynamically switch between functional phenotypes; effector-like proliferation is unnecessary, and effector-like cells may upregulate inhibitory receptors linked to exhaustion.