Programmed albumin nanoparticles regulate immunosuppressive pivot to potentiate checkpoint blockade cancer immunotherapy
Liandong Feng, Li Yang, Longjie Li, Junying Xiao, Nana Bie, Chao Xu, Jun Zhou, Hongmei Liu, Lu Gan, Yuzhou Wu
Abstract
The therapeutic efficacy of programmed cell death protein 1/programmed cell death-ligand 1 (PD-1/PD-L1) blockade immunotherapy is extremely dampened by complex immunosuppressive mechanisms including regulatory T cells (Treg), M2 macrophages (M2), and prostaglandin E2 (PGE2). The pivotal roles of PGE2 have been recognized by directly inactivating CD8+ T cells and indirectly inducing Treg and M2. Therefore, PGE2 abolishment through inactivating cyclooxygenase-2 (COX-2) could be robust to sensitize tumour toward anti-PD-1/PD-L1 immunotherapy, which has gone into clinical trials. However, exploring this promising strategy in nanomedicine to enhance immunotherapy remains unrevealed. The key challenge to synergistically combine COX-2 inhibition and anti-PD-1/PD-L1 lies in the different pharmacokinetic profiles and the spatial obstacles since PD-1/PD-L1 interaction occurs extracellularly and COX-2 locates intracellularly. Thus, the programmed release nanoparticles (termed as Cele-BMS-NPs) are rationally designed, which are composed of pH-sensitive human serum albumin derivative, BMS-202 compound as PD-1/PD-L1 inhibitor, glutathione (GSH)-activatable prodrug of celecoxib (COX-2 inhibitor). The in vitro experiments demonstrate that this smart Cele-BMS-NPs could extracellularly release BMS-202 under the acidic tumour microenvironment, and the intracellularly release of celecoxib in response to the elevated GSH concentration inside tumour cells. After systemic administration, the intratumoral infiltration of CD8+ T cells is significantly enhanced and meanwhile immunosuppressive M2, Treg, and PGE2 are reduced, thereby eliciting the anti-tumour immune responses toward low immunogenic tumours and postsurgical tumour recurrences.