PDL1 blockade therapy holds great promise in cancer immunotherapy. Ultrasound imaging of PDL1 expression in the tumor is of great importance in predicting the therapeutic efficacy. As a proof-of-concept study, a novel ultrasound contrast agent has been innovated here to image and block PDL1 in the tumor tissue. Briefly, extracellular vesicles (EVs) are engineered to display truncated PD1 (tPD1) on the surface to bind PDL1 with high affinity by fusion to EV-abundant transmembrane protein PTGFRN. The engineered EVs are then encapsulated with Ca(HCO3)2 via electroporation and designated as Gp-EVtPD1, which would recognize PDL1 highly expressed cells and produce gas in the endosomes and lysosomes. On the one hand, the echogenic signal intensity correlates well with the PDL1 expression and immune response inhibition in the tumor. On the other hand, during the trajectory of Gp-EVtPD1 in the recipient cells, tPD1 on the EV binds PDL1 and triggers the PDL1 endocytosis and degradation in endosomes/lysosomes in a sequential manner, and thus boosts the anti-tumor immunity of cytotoxic T cells. In summary, Gp-EVtPD1 serves as a novel ultrasound contrast agent and blocker of PDL1, which might be of great advantage in imaging PDL1 expression and conquering immune checkpoint blocker resistance.
Illustration of Gp-EVtPD1 based ultrasound imaging of PDL1
In Gp-EVtPD1, tPD1-PTGFRN fusion protein modification enabled the EVs to target PDL1 expressed in the tumor, and Ca(HCO3)2 loaded internally empowers the EVs with the characteristic of gas production and thus echogenic capacity when endocytosed by recipient cells. Meanwhile, Gp-EVtPD1 also serves as a degrader of PDL1 and is of great advantage in conquering immune checkpoint blocker resistance.