title: Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells.
abstract: The liver represents a major and frequently sole site of metastases for many types of cancer, particularly gastrointestinal cancers. We showed previously that coadministration of an engineered hepatic-targeting Listeria monocytogenes (LM) with a cancer vaccine enhanced the antitumor effect of vaccine-induced T cells selectively against hepatic metastases. Here, we show that administration of multiple doses of LM, in the absence of vaccine, generates therapeutic responses against hepatic metastases. LM treatment of mice bearing hepatic metastases induced tumor-specific CD8+ T-cell responses that were enhanced by depletion of regulatory T (Treg) cells by either anti-CD25 or cyclophosphamide treatment. Antitumor activity of LM further depended on natural killer (NK) cell activation but was inhibited by presence of a subset of NK T cells. These results show the utility of LM in the treatment of hepatic metastases even in the absence of vaccine administration and further suggest that blockade of Treg cells and NK T cells will enhance antitumor activity.
authors.affiliation: Department of Surgery and Immunology and Hematopoiesis Division, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Lindsay S
authors.initials: LS
authors.lastname: Laird
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Chia
authors.forename: Kristen F
authors.initials: KF
authors.lastname: Meckel
authors.forename: Jill E
authors.initials: JE
authors.lastname: Slansky
authors.forename: John M
authors.initials: JM
authors.lastname: Thompson
authors.forename: Ajay
authors.initials: A
authors.lastname: Jain
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology / Q000628:therapy*; D003520:Cyclophosphamide / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology*; D008113:Liver Neoplasms / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014613:Vaccines, Attenuated / Q000276:immunology / Q000494:pharmacology
chemical_list: D019496:Cancer Vaccines; D014613:Vaccines, Attenuated; D007371:Interferon-gamma; D003520:Cyclophosphamide