Dynamic interplay between tumour, stroma and immune system can drive or prevent tumour progression

Abstract

In the tumour microenvironment, cancer cells directly interact with both the immune system and the stroma. It is firmly established that the immune system, historically believed to be a major part of the body's defence against tumour progression, can be reprogrammed by tumour cells to be ineffective, inactivated, or even acquire tumour promoting phenotypes. Likewise, stromal cells and extracellular matrix can also have pro-and anti-tumour properties. However, there is strong evidence that the stroma and immune system also directly interact, therefore creating a tripartite interaction that exists between cancer cells, immune cells and tumour stroma. This interaction contributes to the maintenance of a chronically inflamed tumour microenvironment with pro-tumorigenic immune phenotypes and facilitated metastatic dissemination. A comprehensive understanding of cancer in the context of dynamical interactions of the immune system and the tumour stroma is therefore required to truly understand the progression toward and past malignancy.

Keywords: T cell; cancer; extracellular matrix; fibroblast; macrophage; mechanical; microenvironment.

Figure 1. Tripartite interaction within tumour ecosystem

Tumour cell behaviour is strongly influenced by the dynamic interactions between the cancer cells themselves, the cells of the immune system, and the tumour stroma—a broad category containing the extracellular matrix (ECM), stromal cells, and intracellular signalling species. The cancer cells, through aberrant signalling and uncontrolled growth, produce a unique microenvironment which results in differential behaviours on the part of both immune and stromal cells. Stromal cells act to reshape the microenvironment in favour of continued tumour progression and express growth factors and inflammatory cytokines. Additionally, cancer cells engage the ECM physically and reshape the ECM mechanically and enzymatically through MMPs and other ECM-remodelling enzymes. Through signalling interactions with immune cells the tumour is able to suppress the anti-cancer immune response and induce the immune cells to secrete pro-inflammatory factors, as well as growth and survival signals which aid tumour progression.

Figure 2. Summary of stromal conditions, species, and cells affecting and affected by cancer cell activity

Within the tumour stroma, environmental conditions, mechanical forces and extracellular matrix (ECM) structure, stromal cell activity, and the activity of various extracellular signalling molecules and enzymes all affect and are affected by cancer cell activity. Environmental conditions like pH and microenvironmental oxygen content affect cancer cell metabolism, but are also heavily influenced by cancer cell activity. Cancer cells also mechanically interact with the surrounding ECM and modulate their behaviour according to ECM mechanical properties such as stiffness and fibre architecture, but also respond to dynamic stimuli such as mechanical forces conducted through the ECM and interstitial flows and pressures. Furthermore, the integrins through which the cancer cells form focal adhesions with the ECM structure can initiate signalling pathways within the cancer cells in addition to conduction mechanical forces. The activity of stromal cells, such as the fibroblast pictured above, are heavily affected by cancer paracrine signalling in the tumour microenvironment, but also can change the physical and signalling characteristics of the microenvironment, both of which are significant determinants of cancer cell behaviour. The activity of signalling molecules, such as the pictured cytokines but also growth and survival factors, within the tumour microenvironment are also important determinants of not only cancer cell behaviour but also of stromal and immune cell (not pictured) behaviour. Finally, enzymatic activity, such as that of matrix metalloproteinases (MMPs), can shape the tumour microenvironment both physically and chemically, both of which can greatly affect cancer cell behaviour.

Figure 3. Summary of selected immune cells’ aberrant functions in cancer

For each cell type, the associated immune subsystem (adaptive or innate immune response), aberrant function in cancer, and whether the disruption is from an increase or disruption in normal function is given.

Figure 4. Macrophage positive-feedback effect on tumour ECM stiffening

Macrophages are recruited to the tumour stroma through CCL2 secretion and SMAD upregulation in CAFs. Once recruited, these macrophages secrete TGF-β which stimulates the production of collagen and LOX by the tumour stroma which in turn leads to fibrosis and tumour ECM stiffening.