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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

Preprint posted on 23 April 2020 https://www.biorxiv.org/content/10.1101/2020.04.21.051615v1

Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-021-22985-5

T cells- Dancing on the grooves

Selected by Ankita Jha

Context:

Extra-cellular matrix (ECM) environments influence cell-migration by providing contact guidance for cells. ECM architecture and stiffness can influence different migratory phenotypes and this phenotypic switching is important for cells to navigate through ECM. Cancer cells utilize phenotypic switching to migrate out of the tumors and undergo metastasis. However, T cells need to effectively infiltrate into the solid tumors and how T cells migrate through complex ECM environments remains to be elucidated (Best et al., 2019; Ray et al., 2017; Provenzano et al., 2006a, 2008b; Tabdanov et al., 2018a, 2018b.)

Major findings:

To understand how T cells migrate through varied ECM architecture and stiffness, the authors have utilized engineered platforms with nano-topography of ‘ridges and grooves’ and variable stiffness, mimicking ECM architecture and mechanical environment respectively. Experiments show that T cells with higher contractility tend to invade in the grooves (similar to pseudopodia, more amoeboid like) whereas cells with relatively lower contractility tend to be less invasive and spread more on the ridges (more mesenchymal-like). With the increase in rigidity of the substrate, the amoeboid invasiveness of the T cells goes down. Cells with higher contractility show strong contact guidance with persistent directional migration. This is regulated by microtubule dynamics where microtubule de-stabilization leads to increase invasiveness. This is corroborated with the findings that microtubule destabilization leads to an increase in contractility by releasing GEF-H1 (Rho-GEF) that activates RhoA pathway. This was shown to be analogous with human CD4+ T cells and cytotoxic mouse T cells migrating in a more complex 3D micro-environment. GEF-H1 knock-out in the presence of microtubule destabilization leads to a decrease in motility suggesting the role of GEF-H1 in regulating the contractility axis and thus T cell motility.

What’s next and my questions to the authors:

Immunotherapy with targeted T cells has to overcome the challenges of complex micro-environment like low pH, lack of nutrients along with the physical barriers, and heterogeneity in the solid tumors. This work focusses on tackling the complexity of ECM architecture and mechanics by perturbing the microtubule-contractility axis and modulating RhoA activity. Microtubule destabilization leads to an increase in the contractility and authors show that this is via GEF-H1, however, GEF-H1 knockdown leads to an increase in the motility of T cells. This seems a little surprising since GEF-H1 knockdown would decrease contractility, I wonder if authors have thoughts about it? Plasticity in the modes of migration is based on the balance between contractility and adhesion, do the authors think one important feature to consider along with the ECM architecture and mechanics would be the availability of adhesive ligands? Do microtubules impact cortical tension and would impact the invasiveness?

References:

Best, S.L., Liu, Y., Keikhosravi, A., Drifka, C.R., Woo, K.M., Mehta, G.S., Altwegg, M., Thimm, T.N., Houlihan, M., Bredfeldt, J.S., et al. (2019). Collagen organization of renal cell carcinoma differs between low and high grade tumors. BMC Cancer 19, 490.

Provenzano, P.P., Eliceiri, K.W., Campbell, J.M., Inman, D.R., White, J.G., and Keely, P.J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4, 38.

Provenzano, P.P., Inman, D.R., Eliceiri, K.W., Trier, S.M., and Keely, P.J. (2008). Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95, 5374–5384.

Tabdanov, E.D., Puram, V.V., Win, Z. et al. Bimodal sensing of guidance cues in mechanically distinct microenvironments. Nat Commun 9, 4891 (2018)

Tabdanov ED, Puram V, Zhovmer A, Provenzano PP. Microtubule-Actomyosin Mechanical Cooperation during Contact Guidance Sensing. Cell Rep. 2018;25(2):328‐338.e5.

Tags: cell biology, cell migration, immune, immunotherapy, microtubules

Posted on: 3 June 2020 , updated on: 4 June 2020

doi: https://doi.org/10.1242/prelights.21633

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Author's response

Erdem Tabdanov shared

Thank you, Ankita! We are very glad that our study interested the scientific community, and in particularly the cell biology auditorium. We are grateful for highlighting our preprint for a wider attention across many fields in biology and biophysics.

Indeed, the principles of 3D cell motility are becoming the next frontier towards understanding the very principles of multicellular organisms organization. More importantly, at this stage, these study inform us more on how immune cells navigate and survey for the pathogen and cancer cells. A deeper, mechanistic understanding will enable us to engineer immune cells with biophysical properties, better suited to target solid tumors, currently impenetrable for the T and NK cells to eliminate the malignant cells.

We hope that this study will become a step towards the novel engineering principles of 3D cell motility.

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