2025 Theses Doctoral

T cell fate in the solid tumor microenvironment

Schultheiss, Paula Josefine

T cell-based immunotherapies have transformed treatment for hematological cancers, yet their efficacy in solid tumors remains limited. Mechanical cues within the tumor microenvironment influence T cell function, but their role in shaping T cell fate is poorly understood.

This thesis investigates how substrate and tissue stiffness affect T cell activation, proliferation, and phenotype, with a focus on mechanosensitive expansion ex vivo and tumor stiffness in vivo. To address variability in mechanosensitive responses, we analyzed primary human T cells from healthy donors, assessing their proliferation on substrates of different stiffnesses. Flow cytometry and transcriptomic profiling revealed that effector T cells (TEff) mediate mechanosensitive expansion. Depleting TEff cells abolished the stiffness-dependent response, highlighting their central role in promoting cell proliferation of other subtypes via cytokine-mediated signaling in a mechanosensitive manner.

Further, single-cell RNA sequencing identified subset-specific transcriptional changes induced by mechanical signals. Extending these findings to the in vivo setting, we mapped tumor stiffness in murine and human tumor samples and developed a framework for integrating spatial stiffness maps with spatial transcriptomics to analyze the impact of tissue stiffness on T cell gene expression in vivo. Herein we present the first in vivo generated mechanosensitive signature of T cells in tumors. These results establish a mechanobiological framework for optimizing T cell expansion and improving immunotherapy for solid tumors.