Engineered nanomedicines block the PD-1/PD-L1 axis for potentiated cancer immunotherapy

Abstract

Immunotherapy, in particular immune checkpoint blockade (ICB) therapy targeting the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis, has remarkably revolutionized cancer treatment in the clinic. Anti-PD-1/PD-L1 therapy is designed to restore the antitumor response of cytotoxic T cells (CTLs) by blocking the interaction between PD-L1 on tumour cells and PD-1 on CTLs. Nevertheless, current anti-PD-1/PD-L1 therapy suffers from poor therapeutic outcomes in a large variety of solid tumours due to insufficient tumour specificity, severe cytotoxic effects, and the occurrence of immune resistance. In recent years, nanosized drug delivery systems (NDDSs), endowed with highly efficient tumour targeting and versatility for combination therapy, have paved a new avenue for cancer immunotherapy. In this review article, we summarized the recent advances in NDDSs for anti-PD-1/PD-L1 therapy. We then discussed the challenges and further provided perspectives to promote the clinical application of NDDS-based anti-PD-1/PD-L1 therapy.

Keywords: PD-1/PD-L1 axis; cancer immunotherapy; immune checkpoint blockade; nanomedicine; nanosized drug delivery systems..

Fig. 1. Schematic illustration of NDDS-based anti-PD-1/PD-L1 therapy to circumvent immune evasion and elicit a T-cell antitumor immune response.

Inhibitors, nucleic acids and antibodies are therapeutic cargoes loaded in NDDSs. Among different therapeutic strategies targeting the PD-1/PD-L1 axis, 4 unique strategies are highlighted in this review, including a restraining the extracellular secretion of PD-L1-expressing exosomes by delivering small molecular inhibitors (e.g., GW4869) [57]. b Dimerizing PD-L1 on the surface of the tumour cells by delivering small molecular inhibitors (e.g., BMS-1) [54]. c Downregulating PD-1/PD-L1 expression by delivering gene-editing tools or inhibitors (PD-1 downregulation is omitted in the scheme) [55, 74, 88]. d Blocking the PD-1/PD-L1 interaction by antibodies or engineered cellular vesicles [56, 58].

Fig. 2. Schematic demonstration of a tumour-targeted multifunctional prodrug nanovesicle (termed GPR@Doxy/JQ1) for inhibiting MHC-I autophagy and PD-L1-based immune evasion of tumour cells.

a Chemical structure of the main components integrated into the nanovesicles. b Systemic codelivery of Doxy and JQ1 with the nanovesicles for tumour-specific autophagy inhibition and PD-L1 downregulation. c Flow cytometric quantification of Doxy-mediated MHC-I restoration. d PD-L1 expression on the surface of 4T1 tumours in vivo. e Growth curves of the 4T1 breast tumours after various treatments (G1, PBS; G2, GPR@Doxy+Laser; G3, GPR@JQ1 + Laser; G4, GPR@Doxy/JQ1 + Laser) (^***P < 0.001, ^****P < 0.0001). Adapted with permission from [74]. Copyright (2021) John Wiley & Sons, Inc.

Fig. 3. Nucleic acid-loaded NDDSs for anti-PD-1/PD-L1 therapy.

a Preparation of siRNA and PPa-coloaded micelleplexes. b Mechanism of micelleplex-enhanced antitumor efficacy via RNAi of PD-L1 and PDT. Adapted with permission from [55]. Copyright (2016) American Chemical Society. c Schematic illustration of the ANP/plasmid nanoparticles for photothermal genome editing of PD-L1. Adapted with permission from [88]. Copyright (2021) John Wiley & Sons, Inc.

Fig. 4. Schematic illustration of the NDDS integrating anti-PD-1/PD-L1 antibodies for ICB therapy.

a Self-assembly of the S-αPD-L1/ICG@NP nanoparticles. b Quantification of the tumour-infiltrating CD8⁺ T cells after different treatments. c Proliferation assay of the tumour-infiltrating CD8⁺ T cells. d Frequency of TNF-α and IFN-γ dual-positive CD8⁺ T cells (1, PBS; 2, αPD-L1; 3, S-ICG@NP; 4, S-ICG@NP + laser; 5, αPD-L1/ICG@NP; 6, αPD-L1/ICG@NP + laser; 7, S-αPD-L1/ICG@NP; 8, S-αPD-L1/ICG@NP + laser) (^*P < 0.05, ^**P < 0.01, ^***P < 0.001). Adapted with permission from [56]. Copyright (2019) American Association for the Advancement of Science. e P-αPD-L1 for the treatment of residual cancer cells in the primary tumour resection sites. Adapted with permission from [102]. Copyright (2017) Springer Nature.

Fig. 5. Schematic illustration of the CVs for blocking immune checkpoints and achieving tumour-targeted therapeutic delivery.

a Procedure to prepare Fus-CVs. b Mechanistic illustration of the Fus-CVs coblocking PD-L1 and CD47 of the tumour cells. Adapted with permission from [58]. Copyright (2021) John Wiley & Sons, Inc. c Procedure to prepare LyP1-OMV@PD-1. Adapted with permission from [109]. Copyright (2022) John Wiley & Sons, Inc.