TY - JOUR
T1 - Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments
AU - Tabdanov, Erdem D.
AU - Rodríguez-Merced, Nelson J.
AU - Cartagena-Rivera, Alexander X.
AU - Puram, Vikram V.
AU - Callaway, Mackenzie K.
AU - Ensminger, Ethan A.
AU - Pomeroy, Emily J.
AU - Yamamoto, Kenta
AU - Lahr, Walker S.
AU - Webber, Beau R.
AU - Moriarity, Branden S.
AU - Zhovmer, Alexander S.
AU - Provenzano, Paolo P.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105953115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105953115&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22985-5
DO - 10.1038/s41467-021-22985-5
M3 - Article
C2 - 33990566
AN - SCOPUS:85105953115
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2815
ER -