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

doi:10.1038/s41467-021-22985-5

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 journal › Article › peer-review

79 Scopus citations

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 language	English (US)
Article number	2815
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22985-5
State	Published - Dec 1 2021

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).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1038/s41467-021-22985-5

Find It

Find It at U of M Libraries

Cite this

Tabdanov, E. D., Rodríguez-Merced, N. J., Cartagena-Rivera, A. X., Puram, V. V., Callaway, M. K., Ensminger, E. A., Pomeroy, E. J., Yamamoto, K., Lahr, W. S., Webber, B. R., Moriarity, B. S., Zhovmer, A. S., & Provenzano, P. P. (2021). Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments. Nature communications, 12(1), Article 2815. https://doi.org/10.1038/s41467-021-22985-5

Tabdanov, ED, Rodríguez-Merced, NJ, Cartagena-Rivera, AX, Puram, VV, Callaway, MK, Ensminger, EA, Pomeroy, EJ, Yamamoto, K, Lahr, WS, Webber, BR , Moriarity, BS, Zhovmer, AS & Provenzano, PP 2021, 'Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments', Nature communications, vol. 12, no. 1, 2815. https://doi.org/10.1038/s41467-021-22985-5

@article{71ae488e6758458392b3d37a417120a8,

title = "Engineering T cells to enhance 3D migration through structurally and mechanically complex tumor microenvironments",

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.",

author = "Tabdanov, {Erdem D.} and Rodr{\'i}guez-Merced, {Nelson J.} and Cartagena-Rivera, {Alexander X.} and Puram, {Vikram V.} and Callaway, {Mackenzie K.} and Ensminger, {Ethan A.} and Pomeroy, {Emily J.} and Kenta Yamamoto and Lahr, {Walker S.} and Webber, {Beau R.} and Moriarity, {Branden S.} and Zhovmer, {Alexander S.} and Provenzano, {Paolo P.}",

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{\textquoteright}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 Marqu{\'e}s, 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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22985-5",

language = "English (US)",

volume = "12",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

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 - 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).

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 -

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

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Light Microscopy

University Imaging Centers

Cite this

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

Abstract

Bibliographical note

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

University Assets

Light Microscopy

University Imaging Centers

Cite this