PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

Abstract

Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin-granulocyte-macrophage-colony stimulating factor (SA-GM-CSF) surface-modified bladder CSCs vaccine previously developed using our protein-anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling in tumor microenvironment results in tumor-adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8 T cells, a part of these CD8 T cells expressed PD-1. Moreover, the CSCs vaccine upregulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1 blockade to the CSCs vaccine therapy increased the population of CD4 , CD8 and CD8 IFN-γ but not CD4 Foxp3 T cells and induced the highest production of IFN-γ. PD-1 blockade could effectively enhance the functions of tumor-specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM-1 cell challenge. These results indicate that PD-1 blockade combined with the GM-CSF-modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.

Emerging Roles of Cancer Stem Cells in Bladder Cancer Progression, Tumorigenesis, and Resistance to Chemotherapy: A Potential Therapeutic Target for Bladder Cancer

“…Shi et al developed urothelial CSC vaccine (streptavidin-granulocyte-macrophage-colony stimulating factor surface-modified bladder CSCs) which effectively induced specific immune response for eliminating bladder CSCs [142]. In the paper, they also showed that the combination therapy of PD-1 blockade and CSC vaccine therapy elevated the population of CD4 + , CD8 + , and CD8 + IFN-γ + cells, which leads to the enhancement of the functions of tumor-specific T lymphocytes and elimination of bladder CSCs [142].…”

Nanoparticle‐Based Nanomedicines to Promote Cancer Immunotherapy: Recent Advances and Future Directions

“…On the other hand, knockdown of PD‐1/PD‐L1 expression also magnifies the efficacy of traditional therapeutic approaches by reducing the immune resistance of tumor tissues . Wang et al utilized small interfering RNA (siRNA) silencing PD‐L1 pathway to break the self‐protecting mechanism of tumor cells against the host immunity, thus boosting the therapeutic efficacy of photodynamic therapy and inhibiting the growth of both existing and metastatic tumors .…”

Strategies of Combination Drug Delivery for Immune Checkpoint Blockades

“…The FCM analysis showed that the amount of mature DCs was significantly higher (6.62 ± 1.28%) in the mice treated with MCSC vaccine than other three groups, including phosphate buffered saline (PBS) group (1.75 ± 0.26%), ethanol‐fixed MCSCs group (2.16 ± 0.12%), and SA‐GM‐CSF group (3.08 ± 0.73%). It was demonstrated that the combined therapy of MCSC vaccine and PD‐1 blockade enhanced specific immune response against MCSCs, and 60% of mice were tumor free on day 45 after immunotherapy . Ali et al fabricated a poly(lactide‐ co ‐glycolide) (PLG) cancer vaccine containing GM‐CSF and CpG‐ODN to coordinate the recruitment and antitumor programming of DCs.…”