Figure 2.

Potential immunosuppressive mechanisms of TEX in the context of immunotherapy resistance. TEX-bound CD73/CD39 can turn extracellular ATP into adenosine. Adenosine is a molecule possessing immunosuppressive properties in the TME. Adenosine binding to adenosine receptors (A2R, A2BR) on T-cells can directly inhibit T-cell activation. Adenosine also promotes differentiation of macrophages toward an M2-like phenotype. Prostaglandin E2 (PGE2)-containing TEX can also stimulate production of CD73 and subsequently adenosine by DCs, by activating PGE2 receptors (EP2, EP4). This results in an additional adenosine production. Moreover, TEX-bound TIM-3, upon phagocytosis by macrophages, can promote transition of the latter to a pro-tumoral M2-like phenotype. TEX-bound galectin-9 can promote apoptosis of T-helper cells (Th1) by binding to TIM-3 on the latter. TEX-bound galectin-9 can also promote the conversion of myeloid cells into tumor-favorable MDSCs by inducing the secretion of IL-6, IL-1β, and other cytokines by nasopharyngeal carcinoma cells and myeloid cells. Additionally, TEX-bound PD-L1 can inhibit activation, proliferation, and migration of effector T-cells such as CD4⁺ and CD8⁺.