Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 9, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022830118
Keywords
EpCAM aptamer; gene knockdown; immunotherapy; checkpoint blockade; CD47
Categories
Funding
- National Cancer Institute Cancer Center Support Grant [NIH 5 P30 CA06516]
- NIH [R01CA184718]
- Department of Defense Breast Cancer Breakthrough Fellowship Award [W81XWH-19-1-0039]
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New cancer immunotherapy strategies using EpCAM aptamer-linked small-interfering RNA chimeras (AsiCs) were effective in selectively knocking down genes in EpCAM(+) tumors to enhance immune recognition. Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) were able to inhibit tumor growth and improve tumor-infiltrating immune cell functions. AsiC mixtures showed better efficacy than individual AsiC and could synergize with anti-PD-1 checkpoint inhibition.
New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM(+) tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2(+) orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti-PD-1 checkpoint inhibition.
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