Collagen VI deposition mediates stromal T cell trapping through inhibition of T cell motility in the prostate tumor microenvironment

Hawley C Pruitt; Ya Guan; Hudson Liu; Alexis E Carey; W Nathaniel Brennen; Jiayun Lu; Corrine Joshu; Ashani Weeraratna; Tamara L Lotan; T S Karin Eisinger-Mathason; Sharon Gerecht

doi:10.1016/j.matbio.2023.06.002

Collagen VI deposition mediates stromal T cell trapping through inhibition of T cell motility in the prostate tumor microenvironment

Matrix Biol. 2023 Aug:121:90-104. doi: 10.1016/j.matbio.2023.06.002. Epub 2023 Jun 16.

Authors

Affiliations

¹ Institute for NanoBioTechnology, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA.
² Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA.
³ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁴ Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁵ Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
⁶ Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, The Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁷ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Institute for NanoBioTechnology, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA. Electronic address: sharon.gerecht@duke.edu.

PMID: 37331435
DOI: 10.1016/j.matbio.2023.06.002

Abstract

The tumor extracellular matrix (ECM) is a barrier to anti-tumor immunity in solid tumors by disrupting T cell-tumor cell interaction underlying the need for elucidating mechanisms by which specific ECM proteins impact T cell motility and activity within the desmoplastic stroma of solid tumors. Here, we show that Collagen VI (Col VI) deposition correlates with stromal T cell density in human prostate cancer specimens. Furthermore, motility of CD4+ T cells is completely ablated on purified Col VI surfaces when compared with Fibronectin and Collagen I. Importantly, T cells adhered to Col VI surfaces displayed reduced cell spreading and fibrillar actin, indicating a reduction in traction force generation accompanied by a decrease in integrin β1 clustering. We found that CD4+ T cells largely lack expression of integrin α1 in the prostate tumor microenvironment and that blockade of α1β1 integrin heterodimers inhibited CD8+ T cell motility on prostate fibroblast-derived matrix, while re-expression of ITGA1 improved motility. Taken together, we show that the Col VI-rich microenvironment in prostate cancer reduces the motility of CD4+ T cells lacking integrin α1, leading to their accumulation in the stroma, thus putatively inhibiting anti-tumor T cell responses.

Keywords: Collagen VI; Prostate cancer; T cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Movement
Collagen / metabolism
Extracellular Matrix / metabolism
Humans
Integrin alpha1 / metabolism
Male
Prostate
Prostatic Neoplasms* / genetics
Prostatic Neoplasms* / metabolism
Tumor Microenvironment*

Substances

Integrin alpha1
Collagen

Abstract

Publication types

MeSH terms

Substances

Grants and funding