Interactions between cancer-associated fibroblasts and T-cells: functional crosstalk with targeting and biomarker potential

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as a key component of the tumour microenvironment (TME). Cancer-associated fibroblasts are known to play an important role in maintaining and remodelling the extracellular matrix (ECM) in the tumour stroma, supporting cancer progression and inhibiting the immune system's response against cancer cells. This review aims to summarize the immunomodulatory roles of CAFs, particularly focussing on their T-cell suppressive effects. Cancer-associated fibroblasts have several ways by which they can affect the tumour's immune microenvironment (TIME). For example, their interactions with macrophages and dendritic cells (DCs) create an immunosuppressive milieu that can indirectly affect T-cell anticancer immunity and enable immune evasion. In addition, a number of recent studies have confirmed CAF-mediated direct suppressive effects on T-cell anticancer capacity through ECM remodelling, promoting the expression of immune checkpoints, cytokine secretion and the release of extracellular vesicles. The consequential impact of CAFs on T-cell function is then reflected in affecting T-cell proliferation and apoptosis, migration and infiltration, differentiation and exhaustion. Emerging evidence highlights the existence of specific CAF subsets with distinct capabilities to modulate the immune landscape of TME in various cancers, suggesting the possibility of their exploitation as possible prognostic biomarkers and therapeutic targets.

Keywords: Cancer associated fibroblasts (CAF); T-cells; tumour immunity; tumour microenvironment (TME).

Figure 1

Schematic overview of the suppressing effects CAF exerts on tumour immune microenvironment. (Figure prepared using Biorender.com).

Figure 2

The molecular mechanisms of CAF-induced T-cell apoptosis and suppression of T-cell proliferation. (A) Cancer-associated fibroblasts inhibit T-cell proliferation through the secretion of signalling molecules. (B) Increased expression of Presenilin-1 (PS1) in CAFs activates the WNT pathway, leading to the release of IL-1β. This consequently causes activation of EPAS1/iNOs/NO signalling cascade in cytotoxic T-cells, inhibiting their proliferation. (C) DirecT-cell-cell contact between CAFs and T-cells, mediated by PD-L2 and FASL on the surface of CAFs, as well as PD-1 and FAS on T-cells, induces apoptosis in T-cells. (Figure prepared using Biorender.com)

Figure 3

Cancer-associated fibroblasts affect T-cell migration and infiltration. (A) Under the influence of FGF2 secreted by cancer cells, CAFs secrete CXCL16, which together with CXCL12 has a high affinity towards proteoglycans in ECM, and causes imprisonment of T-cells in the ECM not allowing tumour islet infiltration. Cancer-associated fibroblasts secreted CXCL12 blocks INF-γ and TNF-α production by T-cells, impairing their motility and function. (B) Cancer-associated fibroblasts can specifically support migration and infiltration of Tregs through secretion of IL-6, TGF-β and IL-1β. Additionally, CAFs attract and mobilize Tregs through direct cell-cell contact mediated by surface molecules PD-L2, OX40L and JAM2. (C) Through increased production of insoluble components of ECM mediated by hyperactivity of the TGF-β pathway in CAFs, they create a denser ECM matrix that acts as a physical barrier discriminately towards Thc and CTc, allowing survival and infiltration of Tregs. (Figure prepared using Biorender.com)

Figure 4

The molecular mechanism of CAFs affecting T-cell differentiation and exhaustion. (A) Cancer-associated fibroblasts secrete auto-stimulating molecules VEGF and TGF-β, which cause differentiation of Tregs. (B) Cancer-associated fibroblasts-secreted TGF-β also impairs the differentiation of CTc and affects the production of CTc functional molecules such as perforin, granzymes, FASL and INFγ. In addition, TGF-β inhibits Thc and their release of IL-2. (C) IL-6 secreted by CAFs has an inhibitory effect on CTc differentiation and it stimulates the differentiation of Tregs. In addition, it stimulates Thc production of INF-γ and IL-17A. Although this activation still ends up having an inhibitory effect, through INF-γ inducing IDO expression in DC, consequently causing T-cell apoptosis, and inhibiting IL-2 release and T-cell proliferation. (D) Through the direct cell-cell contact mediated by PD-L1 and PD-L2 on CAFs and PD-1 on T cells, CAFs cause Treg differentiation, inhibition of T-cell proliferation and T-cell apoptosis. (E) Through miR-92 containing exosomes, CAFs induce YAP1 nuclear translocation in cancer cells that reduces their expression of LATS2. In return, this causes higher expression of PD-L1 on the surface of cancer cells, which in contact with PD-1 on T-cells causes the same effect as in D. (F) Bidirectional interaction between CAFs and T-cells mediated through causes the higher expression of PD-1 and CD39 on T-cells, inducing the same endpoint effects as in E and D. (Figure prepared using Biorender.com)