Figure 4.

Barriers in the solid tumor microenvironment (TME) that can hinder chimeric antigen receptor (CAR) T-cell activity. In order to mediate an antitumor response, CAR T-cells must first successfully home to and penetrate the tumor bed. Obstacles to these events include tumor chemokine and T-cell chemokine receptor mismatches, and various inhibitory mechanisms in the vasculature such as ICAM-1 downregulation. In the stroma, T-cells can be physically blocked by dense extracellular matrix and by inhibitory cancer-associated fibroblasts. The TME itself is also hostile, comprising a range of inhibitory immune cells, inhibitory receptors such as PD-L1 on tumor cells and immune infiltrate alike, and soluble molecules such as TGFβ that impair T-cell activity (some examples are shown). In addition, the TME is typically acidic, hypoxic, full of toxic metabolites, and nutrient depleted which can inhibit not only T-cell activity but also other immune infiltrate such as DCs that lose their ability to mature and provide support to T-cells. Moreover, some of these conditions promote protumoral immune cells.