The role of MAPK-signaling in T cell activity

Abstract

Dissertation gesperrt bis zum 15.01.2028!

Cancer immunotherapies have become an integral component of modern oncology, providing meaningful clinical benefit in selected patients with advanced malignancies. Immune checkpoint inhibitors (ICIs) have achieved durable responses in entities such as melanoma and non–small cell lung cancer; however, many patients with solid tumors derive limited or transient benefit, underscoring the need for complementary strategies to improve T cell performance. This thesis explores the modulation of intrinsic T cell signaling pathways as a strategy to enhance T cell functionality, focusing on the stress-activated protein kinase (SAPK) pathway and the kinases p38 and MKK4. Using primary human CD4⁺ and CD8⁺ T cells, pharmacological targeting of MAPK pathway components was investigated in the context of ex vivo T cell activation and expansion. Functional and phenotypic properties were assessed using established in vitro culture and cytotoxicity models designed to evaluate sustained T cell activity. By systematically evaluating the impact of MAPK pathway modulation during T cell preparation, this work highlights the translational relevance of small-molecule–based approaches to optimize T cell–based immunotherapies. These findings provide a rationale for further investigation of kinase-targeted strategies in the development of improved T cell therapies for solid tumors.