Development of cancer immunotherapy based on PD-1/PD-L1 pathway blockade

Abstract

Programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy has achieved considerable success in various tumours. However, only a fraction of patients benefit from its clinical application, and some patients might be suffer from tumour resistance against PD-1/PD-L1 blockade therapy after the original response. In this review, we summarized the main reasons that caused the low response rate of PD-/PD-L1 blockade therapy: firstly, the off-target of PD-1/PD-L1 blocking agents, which is also the main factor of the side effect of autoimmune disorders; secondly, the insufficient infiltration of T cells in a tumour microenvironment; thirdly, the low immunogenicity of tumor cells; fourth, other immunosuppressive components impairing the therapeutic efficacy of the immunotherapy based on the PD-/PD-L1 blockade, and introducing some updated the delivery system of PD-1/PD-L1 blocking agents and the combination therapy based on PD-1/PD-L1 inhibitors and other therapeutics that can complement and promote each other to achieve improved immune response.

Fig. 1. Strategies to reduce side effects.

Fig. 2. Schematic illustration of the delivery of aPDL1 to the primary-tumor resection site by platelets. Images were reproduced form ref. 30.

Fig. 3. Schematic illustration of the preparation of PD-1 antibody-target nanoparticles, and its trafficking mechanism to the target spot. Images were partly reproduced form ref. 32.

Fig. 4. Immunosuppression in the tumour microenvironment. Tumour cells secrete immunosuppressive factors such as TGF-β2 and IL-10, all of which suppress the activity of effector T cells. PD-L1 expressed on its surface also suppresses effector T cells activity through PD-1/PD-L1 pathway. COX2, IL-6, GM-CSF and VEGF recruit MDSCs to the tumour microenvironment. Tumour cells secrete CCL22 to recruit Tregs and promote its proliferation. MDSCs and Tregs can suppress the activity of effector T cells via various cytokines.

Fig. 5. Combination treatments of chemotherapy and immunotherapy. Chemotherapeutics increase the sensitivity of tumour cells to cytotoxic T lymphocytes specific killing effect due to the upregulation of M6PR on cells and increase of the permeability of the cells to GrzB secreted by cytotoxic T lymphocytes. Chemotherapeutics induces ICD, resulting in tumour-specific immune response. Chemotherapeutics could decrease Treg and MDSCs levels.