Collagen density regulates the activity of tumor-infiltrating T cells
Top Cited Papers
Open Access
- 12 March 2019
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 7 (1), 68
- https://doi.org/10.1186/s40425-019-0556-6
Abstract
Background Tumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities. Methods T cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis. Results T cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer. Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-β signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells. Conclusions Our study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.Keywords
Funding Information
- Kræftens Bekæmpelse (R124-A7599-15-S2, R149-A9768)
- Novo Nordisk Fonden (NNF16OC0022922)
- Dagmar Marshalls Fond
- Dansk Kræftforsknings Fond
- Einar Willumsen Foundation
This publication has 59 references indexed in Scilit:
- Aligned Collagen Is a Prognostic Signature for Survival in Human Breast CarcinomaThe American Journal of Pathology, 2011
- Imaging Cells in Three‐Dimensional Collagen MatrixCurrent Protocols in Cell Biology, 2010
- An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environmentsThe EMBO Journal, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Matrix Metalloproteinases: Regulators of the Tumor MicroenvironmentCell, 2010
- Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin SignalingCell, 2009
- Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkageOncogene, 2009
- A mechanosensitive transcriptional mechanism that controls angiogenesisNature, 2009
- Cancer immunoediting: from immunosurveillance to tumor escapeNature Immunology, 2002
- The myb gene family in cell growth, differentiation and apoptosisOncogene, 1999