Immunotherapy for breast cancer using EpCAM aptamer tumor-targeted gene knockdown.

Autor:	Zhang Y; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115., Xie X; Department of Pathology, Harvard Medical School, Boston, MA 02115.; Department of Lab Medicine and The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115.; The State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 300020 Tianjin, China., Yeganeh PN; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115., Lee DJ; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115., Valle-Garcia D; Divison of Newborn Medicine and Epigenetics Program, Department of Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Cell Biology, Harvard Medical School, Boston, MA 02115.; Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, 62210 Cuernavaca, México., Meza-Sosa KF; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; Laboratorio de Neuroinmunobiología, Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, 62210 Cuernavaca, México., Junqueira C; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.; René Rachou Institute, Oswaldo Cruz Foundation, 30190-002 Belo Horizonte, Brazil., Su J; Department of Pathology, Harvard Medical School, Boston, MA 02115.; Department of Lab Medicine and The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115.; School of Life Sciences, Center for Bioinformatics, Peking University, 100871 Beijing, China.; Center for Statistical Science, Peking University, 100871 Beijing, China., Luo HR; Department of Pathology, Harvard Medical School, Boston, MA 02115.; Department of Lab Medicine and The Stem Cell Program, Boston Children's Hospital, Boston, MA 02115., Hide W; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115., Lieberman J; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115; judy.lieberman@childrens.harvard.edu.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 02; Vol. 118 (9).
DOI:	10.1073/pnas.2022830118
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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