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Review
. 2020 Nov 11;12(11):3331.
doi: 10.3390/cancers12113331.

Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

Alex Gordon-Weeks  1 , Arseniy E Yuzhalin  2
Affiliations
Review

Cancer Extracellular Matrix Proteins Regulate Tumour Immunity

Alex Gordon-Weeks et al. Cancers (Basel). .

Abstract

The extracellular matrix (ECM) plays an increasingly recognised role in the development and progression of cancer. Whilst significant progress has been made in targeting aspects of the tumour microenvironment such as tumour immunity and angiogenesis, there are no therapies that address the cancer ECM. Importantly, immune function relies heavily on the structure, physics and composition of the ECM, indicating that cancer ECM and immunity are mechanistically inseparable. In this review we highlight mechanisms by which the ECM shapes tumour immunity, identifying potential therapeutic targets within the ECM. These data indicate that to fully realise the potential of cancer immunotherapy, the cancer ECM requires simultaneous consideration.

Keywords: cancer; collagen; extracellular matrix; fibronectin; immune; immune checkpoint; immunity; metastasis; microenvironment; therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Deregulation of ECM homeostasis in cancer affects immune infiltration. Schematic plan illustrating how growing solid tumours form cancer cell nests to educate tissue-resident fibroblasts that acquire a highly synthetic phenotype leading to the production of densely packed structural ECM components. Cancer cells partially contribute to ECM overproduction by secreting certain laminin chains as well as ECM regulators. The mechanisms underlying ECM remodelling in cancer are complex, with the general line being the subtle balance between ECM-decomposing enzymes (mainly MMPs) and their corresponding inhibitors (mainly TIMPs). One of the major consequences of ECM remodelling in cancer is collagen alignment, which partially regulates immune cell trafficking within the tumour microenvironment. Through this and other mechanisms, the cancer ECM excludes some immune cell subsets (such as infiltrating CD8+ T cells) whilst enabling active infiltration of others, such as macrophages and neutrophils. ECM extracellular matrix.
Figure 2
Figure 2
Proposed mechanisms though which the tumour ECM modulates immune cell phenotype and movement (see text for further details). (A) Macrophages in dense matrices demonstrate alternative states of activation dependent on the presence of various ECM glycoproteins. (B) T-lymphocyte phenotype is dependent upon collagen fibre density with loose matrices supporting cytotoxic T-lymphocytes but dense matrices or those incorporating specific glycoproteins leading to immune-inhibitory phenotypes. (C) Neutrophil survival and cytokine production is dependent upon the presence of specific ECM glycoproteins. (D) T-lymphocyte movement is driven by chemokine gradients in loose ECM, but in dense ECMs, T-lymphocytes to not demonstrate chemokine-directed movement. (E) Cancer ECM structure may differentially modulate the migration of T-lymphocytes and macrophages, with only macrophages able to move in dense, highly cross-linked matrices. Collagen fibre matrices demonstrated in black with degrees of density or cross-linking indicated. Arg Arginase, MMP matrix metalloproteinase, GZM granzyme, PRF perforin, INF interferon, TNF tumour necrosis factor, IL interleukin, TGF transforming growth factor, SPARC Secreted Protein Acidic and Rich in Cysteine.
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