Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments

Erdem D. Tabdanov, Nelson J. Rodríguez-Merced, Alexander X. Cartagena-Rivera, Vikram V. Puram, Mackenzie K. Callaway, Ethan A. Ensminger, Emily J. Pomeroy, Kenta Yamamoto, Walker S. Lahr, Beau R. Webber, Branden S. Moriarity, Alexander S. Zhovmer, Paolo P. Provenzano

Research output: Contribution to journalArticlepeer-review

Abstract

Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.

Original languageEnglish (US)
Article number2815
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021
Externally publishedYes

Bibliographical note

Funding Information:
P.P.P. and this work was supported by the NIH (R01CA181385 to P.P.P., U54CA210190 University of Minnesota Physical Sciences in Oncology Center to P.P.P., a supplement to R01CA181385 to E.D.T., and NIAID training grant T32AI997313 to E.J.P.) and by a Research Scholar Grant RSG-14-171-01-CSM from the American Cancer Society. This work was also supported by the Randy Shaver Research and Community Fund (P.P.P.), grants from the UMN Institute for Engineering in Medicine (P.P.P.), and the Children’s Cancer Research Fund (B.S.M and B.R.W.). A.C.R. was supported by the NIH Distinguished Scholars Program and the NIH Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering. A.S.Z. was supported by the NIH Intramural Research Program of the National Heart, Lung, and Blood Institute. We thank the University of Minnesota Imaging Center (UIC) and UIC staff, particularly Dr. Guillermo Marqués, for helpful assistance (https://med.umn.edu/uic). The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.

Publisher Copyright:
© 2021, The Author(s).

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