title: Tumor-associated antigen expressing Listeria monocytogenes induces effective primary and memory T-cell responses against hepatic colorectal cancer metastases.
abstract: OBJECTIVE
  Despite advances in therapy for the treatment of metastatic colorectal cancer, many patients die of hepatic disease. Current immunotherapeutic strategies are likely limited by inhibitory signals from the tumor. To successfully eliminate tumor deposits within an organ, an appropriate immunologic milieu to amplify antitumor responses must be developed.
  
  
  METHODS
  We used a murine model utilizing the CT26 colon cancer cell line to analyze primary and memory tumor-specific T-cell responses induced by an attenuated actin A and internalin B deleted immunodominant tumor-associated antigen expressing strain of Listeria monocytogenes for the treatment of metastatic colorectal cancer.
  
  
  RESULTS
  Treatment of mice bearing established hepatic metastases with this L. monocytogenes strain led to the generation of a strong initial tumor-specific cytotoxic CD8(+) T-cell response that successfully treated 90% of animals. Tumor antigen-specific central and effector memory T cells were also generated and protected against tumor rechallenge. These cell populations, when measured before and after tumor rechallenge, showed a marked expansion of antigen-specific effector CD8(+) effector memory T cells. This strain of L. monocytogenes was able to down-modulate the expression of the immune checkpoint molecule, PD-1, within the tumor microenvironment but had variable effects on CTLA-4 expression.
  
  
  CONCLUSIONS
  This L. monocytogenes strain generated a highly effective antitumor T-cell response, providing a basis for the development of this vaccine platform in patients with liver metastases.
authors: Department of Surgery, Sidney Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors: Kelly
authors: K
authors: Olino
authors: Satoshi
authors: S
authors: Wada
authors: Barish H
authors: BH
authors: Edil
authors: Xiaoyu
authors: X
authors: Pan
authors: Kristen
authors: K
authors: Meckel
authors: Walter
authors: W
authors: Weber
authors: Jill
authors: J
authors: Slansky
authors: Koji
authors: K
authors: Tamada
authors: Peter
authors: P
authors: Lauer
authors: Dirk
authors: D
authors: Brockstedt
authors: Drew
authors: D
authors: Pardoll
authors: Richard
authors: R
authors: Schulick
authors: Kiyoshi
authors: K
authors: Yoshimura
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000378:metabolism; D002277:Carcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D061026:Programmed Cell Death 1 Receptor; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory
chemical_list: D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D018906:Antineoplastic Agents, Alkylating; D060908:CTLA-4 Antigen; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma; D003520:Cyclophosphamide