Obstacles for T-lymphocytes in the tumour microenvironment: Therapeutic challenges, advances and opportunities beyond immune checkpoint

Abstract

The tumour microenvironment (TME) imposes a major obstacle to infiltrating T-lymphocytes and suppresses their function. Several immune checkpoint proteins that interfere with ligand/receptor interactions and impede T-cell anti-tumour responses have been identified. Immunotherapies that block immune checkpoints have revolutionized the treatment paradigm for many patients with advanced-stage tumours. However, metabolic constraints and soluble factors that exist within the TME exacerbate the functional exhaustion of tumour-infiltrating T-cells. Here we review these multifactorial constraints and mechanisms - elevated immunosuppressive metabolites and enzymes, nutrient insufficiency, hypoxia, increased acidity, immense amounts of extracellular ATP and adenosine, dysregulated bioenergetic and purinergic signalling, and ionic imbalance - that operate in the TME and collectively suppress T-cell function. We discuss how scientific advances could help overcome the complex TME obstacles for tumour-infiltrating T-lymphocytes, aiming to stimulate further research for developing new therapeutic strategies by harnessing the full potential of the immune system in combating cancer.

Keywords: Immunotherapy; Ionic checkpoint; Tumor-infiltrating lymphocytes; Tumor-interstitial fluid.

Figure 1

TME factors that suppress T-cell anti-tumour responses. Dying/necrotic tumour cells release significant amounts of intracellular contents, such as K⁺ ions, ATP, and adenosine into the extracellular milieu. In addition, nutrient insufficiency, hypoxia, and altered enzymatic activities increase lactate concentrations creating the TME acidic. These conditions favour the differentiation of suppressive Tregs and tolerogenic DCs; all of which are unfavourable for the anti-tumour functions of infiltrating T-lymphocytes.

Figure 2

Lactic acid buildup in the TME impacting immunological pathways resulting in impaired T-cell anti-tumour response. Hypoxia in the tumour core, over-consumption of glucose, and increased expression of LDH and lactate transporters contribute to the TME acidification. Increased acidity in the TME hampers the function of TILs by multiple mechanisms - inhibiting energy metabolism, upregulating inhibitory receptors (e.g., PD-1), disrupting TCR signalling, and producing immunosuppressive cytokines, enzymes, and signalling proteins (e.g., IL-4, IL-10, CCL5, TGFβ, VEGF). It also inhibits the ability of DCs to prime Th1 cells and skews TAM polarization toward the M2 phenotype. These M2-like TAMs lack the ability of phagocytizing tumour cells and help tumour cells escape from the TIL attack.

Figure 3

TME factors interfering mitochondrial functions of TILs. Continuous hypoxia, metabolic stress and antigen stimulation impede the functional fitness of TIL mitochondria and mitochondrial biogenesis. In addition, they upregulate PD-1, Blimp-1 and PGC1-dependent metabolic reprogramming and depolarize mROS production, while reducing mitochondrial cristae remodelling and OXPHOS pathway. These changes skew bioenergetic signalling, metabolic reprogramming and ion-based pathways rendering TILs exhausted and non-functional.

Figure 4

Major TME purinergic signalling pathways that impair anti-tumour responses of infiltrating T-lymphocytes. Increased soluble and cell membrane-bound ectonucleotidases (CD39 and CD73) increase adenosine levels within the TME. Adenosine induces the production of immunosuppressive cytokines (e.g., IL-10, IL-6, VEGF). It also inhibits the functioning of TAMs and DCs that not only favour tumour progression but hider TIL function (such as proliferation, motility, and cytotoxicity).