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  • Review Article
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CAF-induced physical constraints controlling T cell state and localization in solid tumours

Nature Reviews Cancer volume 24, pages 676–693 (2024)Cite this article

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Abstract

Solid tumours comprise cancer cells that engage in continuous interactions with non-malignant cells and with acellular components, forming the tumour microenvironment (TME). The TME has crucial and diverse roles in tumour progression and metastasis, and substantial efforts have been dedicated into understanding the functions of different cell types within the TME. These efforts highlighted the importance of non-cell-autonomous signalling in cancer, mediating interactions between the cancer cells, the immune microenvironment and the non-immune stroma. Much of this non-cell-autonomous signalling is mediated through acellular components of the TME, known as the extracellular matrix (ECM), and controlled by the cells that secrete and remodel the ECM — the cancer-associated fibroblasts (CAFs). In this Review, we delve into the complex crosstalk among cancer cells, CAFs and immune cells, highlighting the effects of CAF-induced ECM remodelling on T cell functions and offering insights into the potential of targeting ECM components to improve cancer therapies.

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Fig. 1: Cancer-associated fibroblasts comprise diverse subsets, with shared and unique markers.
Fig. 2: Tumour-promoting consequences of cancer-associated fibroblast-mediated extracellular matrix remodelling in cancer.
Fig. 3: Biomechanical effects of extracellular matrix remodelling on tumour immunity.
Fig. 4: Therapeutic strategies to restore tumour immunity through targeting of the tumour extracellular matrix.

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Acknowledgements

The authors thank the Scherz-Shouval laboratory members for helpful discussions. L.A. is funded by the Sergio Lombroso Postdoctoral Fellowship programme. R.S.-S. is incumbent of the Robert and Yadelle Sklare Professorial Chair in Biochemistry.

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  1. Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel

    Ludovica Arpinati, Giulia Carradori & Ruth Scherz-Shouval

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  1. Ludovica Arpinati
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L.A. researched data for the article, contributed substantially to discussion of the content and wrote the article. G.C. researched data for the article, prepared the figures and contributed to discussion of the content and to the writing of the article. R.S.-S. researched data for the article, contributed substantially to discussion of the content and to the writing and reviewed and edited the manuscript before submission.

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Correspondence to Ruth Scherz-Shouval.

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Glossary

Azoxymethane (AOM)–dextran sodium sulfate (DSS)

A standard mouse model for colitis-associated cancer obtained by the chemical induction of DNA damage (via AOM injection) followed by cyclic administration of DSS to induce colonic epithelial damage.

Cholangiocarcinoma

Rare cancer arising from various areas of the biliary duct epithelium, including the intrahepatic, perihilar and extrahepatic areas.

Desmoplastic ECM

High-density ECM surrounding the tumour that results from an increased production and deposition of ECM fibres.

Discoidin domain receptors

(DDRs). Collagen-binding tyrosine kinase receptors that mediate numerous processes such as wound healing, tissue development and cell growth and migration under physiological and pathological conditions including cancer.

ECM scores

A numerical value derived from the expression of a set of ECM-related genes of interest that can be used as a predictive biomarker.

Fibre alignment

The organized orientation of ECM fibres (such as collagen fibres intersecting each other orthogonally) that can direct an organized cell migration and proper focal adhesion.

Gelatinases

Subgroup of secreted MMPs including MMP2 and MMP9 that easily digest gelatin among other ECM molecules.

Glycoproteins

A class of ECM macromolecules containing carbohydrate chains (monosaccharides or oligosaccharides) covalently bound to amino acid side chains.

KPC

Transgenic mouse model of PDAC bearing a pancreas-specific expression of mutant Kras and mutant Trp53 (KrasG12D; Trp53R172H; Pdx1-cre).

KPPC

Transgenic mouse model of PDAC bearing a pancreas-specific expression of mutant Kras and Trp53 (KrasG12D/+; Trp53R172H/R172H; P48-cre).

KPPF model

Transgenic mouse model of PDAC bearing a pancreas-specific Trp53 knockout and pancreas-specific oncogenic Kras expression (KrasFSF-G12D/+; Trp53frt/frt; Pdx1-Flp).

KTC model

Genetically engineered mouse model of PDAC bearing pancreas-selective Tgfbr2 knockout and mutant (G12D) Kras expression (Tgfbr2flox/wt; KrasLSL-G12D/+; Ptf1a-cre).

Laminins

A family of ECM glycoproteins prominent in the basal lamina of tissues that have a major role in promoting cell adhesion by anchoring cells to the ECM.

Lysyl hydroxylase

(LH). Iron-dependent crosslinking enzymes that catalyse the hydroxylation of lysine residues of collagen.

Lysyl oxidase (LOX)

(LOX). Copper-dependent crosslinking enzyme that oxidizes lysine residues of collagen and elastin.

Matrilysins

Subgroup of secreted MMPs with ECM proteolytic activity, such as MMP7 (matrilysin-1) and MMP26 (matrilysin-2).

Matrix metalloproteinases

(MMPs). Secreted or membrane-anchored zinc-dependent endopeptidases that degrade different ECM components.

M0 macrophages

The use of M0 generally refers to a population of macrophages characterized by a non-activated phenotype.

MMTV-PyMT

Transgenic model that leads to the development of spontaneous mammary tumours as a result of the expression of the polyoma middle T (PyMT) oncogene under the control of the mouse mammary tumour virus (MMTV) promoter.

Omental fibroblasts

Fibroblasts present in the omentum, a fatty tissue layer surrounding intraperitoneal organs such as stomach and small intestine.

Proteoglycans

ECM macromolecules highly present in connective tissues and consist of a protein core covalently bound to glycosaminoglycan chains.

Rigidity

Resistance to deformation in response to an applied force that in the context of cancer occurs as a consequence of dysregulated ECM remodelling and increased collagen crosslinking.

Shear stress

In physiology, shear stress refers to the mechanical stress imposed by tangential forces of the blood flow on blood vessel walls and within the TME; cancer cells can experience shear stress owing to the pressure generated by interstitial fluids.

Stromelysins

Subgroup of stromal-cell-derived secreted MMPs including MMP3 (stromelysin-1) and MMP10 (stromelysin-2) that can degrade various matrix components such as proteoglycans and fibronectin.

Viscoelasticity

The ability of a substance to respond in a time-dependent manner to an applied force or stress that induces its deformation.

Viscosity

Resistance to movement or change in shape owing to internal friction that is enhanced in the tumour ECM, facilitating cancer cell motility and dissemination.

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Arpinati, L., Carradori, G. & Scherz-Shouval, R. CAF-induced physical constraints controlling T cell state and localization in solid tumours. Nat Rev Cancer 24, 676–693 (2024). https://doi.org/10.1038/s41568-024-00740-4

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  • DOI: https://doi.org/10.1038/s41568-024-00740-4

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