Cancer-associated fibroblasts: heterogeneity and their role in the tumor immune response

Xiao, Yuxuan; Wang, Ziyu; Gu, Meng; Wei, Panjian; Wang, Xiaojue; Li, Weiying

doi:10.1007/s10238-024-01375-3

Cited by 2 publications

(2 citation statements)

References 95 publications

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“…Within this microenvironment, the ECM extends beyond its structural role, significantly influencing cellular behavior, orchestrating cell signaling, and governing crucial functions such as cell proliferation, motility, and differentiation [5]. As cancer progresses, the TME undergoes significant physical and biochemical changes, including excessive production of ECM components by cancer-associated fibroblasts (CAFs) [6,7] and ECM stiffening due to increased enzymatic cross-linking by lysyl oxidase and enhanced collagen fibril alignment [8][9][10]. These alterations collectively create a distinct mechanical microenvironment that impacts the behavior of cancer cells and stromal cells, especially immune cells and fibroblasts, by modulating their migration and activation within the TME [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Sapudom,

Tipay,

Teo

2024

Preprint

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The tumor microenvironment (TME), which is composed of various cell types and the extracellular matrix (ECM), plays crucial roles in cancer progression and treatment outcomes. However, the impact of the mechanical properties of the ECM, specifically collagen fibril alignment and crosslinking, on macrophage behavior and polarization is less understood. To investigate this, we reconstituted 3D collagen matrices to mimic the physical characteristics of the TME. Our results demonstrated that stiffening the matrix through the alignment or crosslinking of collagen fibrils promotes macrophage polarization toward the anti-inflammatory M2 phenotype. This phenotype is characterized by increased expression of CD105 and CD206 and a distinct cytokine secretion profile. The increased stiffness and aligned fibrils activate mechanotransduction pathways, notably integrin β1 and PI3K signaling, leading to increased IL-4 secretion, which acts in an autocrine manner to further promote M2 polarization. Interestingly, these stiffened microenvironments also suppressed the proinflammatory response. In coculture experiments with breast cancer cell lines (MDA-MB-231 and MCF-7), macrophages within stiffened or aligned matrices significantly increased cancer cell proliferation and invasion. These findings suggest that the mechanical properties of the ECM, specifically its alignment and crosslinking, create a more favorable environment for tumor progression by modulating macrophage activity. Overall, our study underscores the critical role of ECM mechanics in shaping immune cell behavior within the TME, highlighting the potential for therapies that target ECM properties and macrophage polarization to inhibit cancer progression and enhance treatment efficacy.

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Section: Introductionmentioning

confidence: 99%

“…Myofibroblasts are essential for the formation of the ECM, providing structural support to tumors. The ECM supports tumor cell adhesion and migration and contributes to tumor tissue stiffness, which is often linked to a more aggressive tumor phenotype and poor prognosis [6].…”

Section: Introductionmentioning

confidence: 99%

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Sapudom,

Tipay,

Teo

2024

Preprint

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The integrin adhesome and control of anti-tumour immunity

Webb,

Black,

Barth

et al. 2024

Biochemical Society Transactions

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It is widely regarded that the anti-tumour immune response drives clearance of tumours and leads to prolonged survival in patients. However, tumours are adept at reprogramming the surrounding microenvironment to an immunosuppressive milieu to prevent successful immune directed killing. Adhesion of cells to the extracellular matrix is essential for regulating cellular processes such as survival, proliferation and migration. This adhesion is largely conducted via integrins and their related intracellular signalling networks. Adhesion proteins such as focal adhesion kinase (FAK) are expressed in both tumour cells and cells of the surrounding microenvironment, and are often dysregulated in cancers. Recent work has demonstrated that adhesion proteins are contributing to regulation of the immunosuppressive microenvironment within tumours, and could provide a new avenue to target in combination with immunotherapies. Here, we provide an overview of the effort being made to elucidate the roles adhesion proteins play in modulating anti-tumour responses within a variety of cancer settings. In particular we focus on the multifaceted role of FAK within the tumour immune microenvironment. Finally, we summarise the data in clinical trials, where targeting FAK is being exploited to prime the tumour microenvironment and create potent responses when combined with immunotherapies.

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Cancer-associated fibroblasts: heterogeneity and their role in the tumor immune response

Cited by 2 publications

References 95 publications

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

Mechano-mediated M2 macrophage polarization and immune suppression in stiffened tumor microenvironment

The integrin adhesome and control of anti-tumour immunity

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