Matrix alignment and density modulate YAP-mediated T-cell immune suppression

Abstract T-cells navigate through various mechanical environments within the body, adapting their behavior in response to these cues. An altered extracellular matrix (ECM) characterized by increased density and enhanced fibril alignment, as observed in cancer tissues, can significantly impact essential T-cell functions critical for immune responses. In this study, we used 3D collagen matrices with controlled density and fibril alignment to investigate T-cell migration, activation, and proliferation. Our results revealed that dense and aligned collagen matrices suppress T-cell activation through enhanced YAP signaling. By inhibiting YAP signaling, we demonstrated that T-cell activation within these challenging microenvironments improved, suggesting potential strategies to enhance the efficacy of immunotherapy by modulating T-cell responses in dense and aligned ECMs. Overall, our study deepens our understanding of T-cell mechanobiology within 3D relevant cellular microenvironments and provides insights into countering ECM-induced T-cell immunosuppression in diseases such as cancer. Competing Interest Statement The approach to fabricate aligned collagen matrices is intellectually protected (International patent application number PCT/B2024/051112; titled "Noninvasive turning of protein alignment"). Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.