Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression

Abstract

Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.

Keywords: fine-tuning; immunosuppression; immunotherapy; mechanisms; tumour; tumour microenvironment.

Figure 1

The immune circuitry within ‘cold’ tumour niches is governed by soluble factors such as cytokines, growth factors and enzyme-regulated metabolites. Immune and stromal cell types send and receive signals within the tumour milieu which culminates in the generation of an immune privileged TME that impairs anti-tumour immunity. Abbreviations: T2-C: type-II inflammatory cytokines, IDO: indoleamine 2,3-dioxygenase, TGF-B: transforming growth factor β, ADO: adenosine, ARG1: arginase-1, iNOS: inducible nitric oxide synthase, and IL-10: interleukin-10.

Figure 2

The TME perturbs multiple mechanisms of T cell migration to avoid immune surveillance. Cancer cells can impede with CTL trafficking to the tumour bed at multiple levels including the loss of extravasation capacity, disrupted chemokine gradients and physical constraints including increased ECM deposition and poor oxygen availability.

Figure 3

Tumours with intense inflammation may perturb the homeostatic balance of memory-effector T cell populations in the TME. ‘Cold’ tumour niches contain an abundance of canonical immunosuppressive factors that create an immune-privileged TME. Conversely, ‘hot’ tumours that contain excessive amounts of pro-inflammatory factors may disrupt the balance of effector-memory CTL populations, resulting in short-lived effector responses. In contrast, a balance of pro- and anti-inflammatory signals in the TME may endow CTLs with improved cytolytic responses that are long lived.

Figure 4

The cellular composition of ‘hot’ and ‘cold’ tumours. Anti-tumour immunity in the TME depends on the presence of CTLs that are activated by endogenous IFN-I and other pro-inflammatory stimuli produced by neighbouring cells. However, these can be subverted by an imbalance of anti-inflammatory factors that also reduces their trafficking to the tumour site. Conversely, too much inflammation may impair the cytolytic activities of CTLs, triggering immune escape. This intense inflammation mediated by conventional anti-tumour factors such as IFN-Is also upregulate T cell inhibitory molecules (TCIMs) on tumour cells that drive the adaptive resistance to immunotherapy.