Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown
Ying Zhang, Xuemei Xie, Pourya Naderi Yeganeh, Dian-Jang Lee, David Valle‐García, Karla F. Meza‐Sosa, Caroline Junqueira, Jiayu Su, Hongbo R. Luo, Winston Hide, Judy Lieberman
Abstract
Significance Immunotherapy benefits some aggressive breast cancers, but many breast tumors do not respond to checkpoint blockade. Novel strategies to increase breast cancer immunogenicity are needed to improve immunotherapy. Here, we used epithelial cell adhesion molecule (EpCAM) aptamer-linked small-interfering RNA chimeras (AsiC) to selectively knock down genes in mouse breast cancers to induce tumor neoantigens or overcome immune evasion. Individual gene knockdown markedly delayed tumor growth and enhanced antitumor immunity. Cd47 and Parp1 AsiCs outperformed anti-CD47 antibody and the PARP1 inhibitor Olaparib, respectively. Combining EpCAM-AsiCs targeting multiple pathways worked better than single agents and enhanced tumor inhibition by a checkpoint inhibitor. EpCAM-AsiCs have the potential to boost immunity to tumors that are poorly responsive to checkpoint blockade.