Taking a cue from the emerging data on tissue-specific effects on T cell phenotypes, Adu-Berchie and Liu et al. found that viscoelasticity (time-dependent response to stress), but not stiffness, impacted T cell RNA signatures (comparing tumor, adjacent normal tissue, or blood), and this could be recapitulated in vitro with specially cross-linked collagen matrices. Short-term activation of T cells, including CAR T cells, exposed to “slow-relaxing” matrices durably imprinted a transcriptome enriched in transcription factors in the AP-1 family, and a phenotype with enhanced in vitro and in vivo killing capability and effector molecule expression. Long-term “chronic” activation abrogated these effects.
Contributed by Ed Fritsch
ABSTRACT: The efficacy of adoptive T-cell therapies largely depends on the generation of T-cell populations that provide rapid effector function and long-term protective immunity. Yet it is becoming clearer that the phenotypes and functions of T cells are inherently linked to their localization in tissues. Here we show that functionally distinct T-cell populations can be generated from T cells that received the same stimulation by altering the viscoelasticity of their surrounding extracellular matrix (ECM). By using a model ECM based on a norbornene-modified collagen type I whose viscoelasticity can be adjusted independently from its bulk stiffness by varying the degree of covalent crosslinking via a bioorthogonal click reaction with tetrazine moieties, we show that ECM viscoelasticity regulates T-cell phenotype and function via the activator-protein-1 signalling pathway, a critical regulator of T-cell activation and fate. Our observations are consistent with the tissue-dependent gene-expression profiles of T cells isolated from mechanically distinct tissues from patients with cancer or fibrosis, and suggest that matrix viscoelasticity could be leveraged when generating T-cell products for therapeutic applications.
Author Info: (1) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University
Author Info: (1) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (2) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (3) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (4) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (5) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (6) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Preventative and Restorative Sciences, School of Dental Medicine, and Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. (7) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (8) Harvard Medical School, Boston, MA, USA. (9) John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. mooneyd@seas.harvard.edu. The Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. mooneyd@seas.harvard.edu.
