title: Synergistic anticancer effects of Pam3CSK4 and Ara-C on B-cell lymphoma cells.
abstract: OBJECTIVE
  The low immunogenicity of many cancer cells and the immunosuppression by various cancers and anticancer therapies have been an obstacle in the development of efficacious immunotherapies. Our goal was to test whether Toll-like receptor (TLR) agonists and anticancer chemotherapeutic agents synergize in rendering tumor cells more immunogenic.
  
  
  METHODS
  We treated B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 and the genotoxic anticancer agent 1-β-D-arabinofuranosylcytosine (Ara-C). The effects on the immunogenicity of tumor cells were measured in transfer experiments and in vitro studies.
  
  
  RESULTS
  The treatment of B-cell lymphoma cells with the TLR1/2 agonist Pam3CSK4 enhanced the anticancer effects of the genotoxic agent Ara-C. Mice injected with cotreated tumor cells survived longer than mice challenged with Pam3CSK4 or Ara-C-treated cells. Administration of Pam3CSK4 or Ara-C reduced the tumor load of mice injected with tumor cells. Cotreatment had no effect on the rate of apoptosis or proliferation of Ara-C-treated cells, but upregulated the expression of several immunomodulatory molecules. Consistent with an increased immunogenicity of Pam3CSK4 and Ara-C-treated B-cell lymphoma cells, rejection of cotreated tumor cells required natural killer cells and T cells. We demonstrate that the upregulation of immunomodulatory molecules in response to Pam3CSK4 and Ara-C depended in part on NF-κB.
  
  
  CONCLUSIONS
  TLR agonists can increase the efficacy of conventional cancer therapies by altering the immunogenicity of B-cell lymphoma cells.
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and.
authors.forename: Sae-Kyung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
authors.forename: Jyh Y
authors.initials: JY
authors.lastname: Chwee
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and.
authors.forename: Cheryl A P
authors.initials: CA
authors.lastname: Ma
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and.
authors.forename: Nina
authors.initials: N
authors.lastname: Le Bert
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and.
authors.forename: Caleb W
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Authors' Affiliations: Immunology Programme, Centre for Life Sciences, Department of Microbiology; and NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore micsg@nus.edu.sg.
authors.forename: Stephan
authors.initials: S
authors.lastname: Gasser
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D016000:Cluster Analysis; D003561:Cytarabine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D054503:Lymphoid Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000819:agonists
chemical_list: D000964:Antimetabolites, Antineoplastic; D055666:Lipopeptides; D016328:NF-kappa B; C508075:Pam(3)CSK(4) peptide; D051195:Toll-Like Receptor 2; D003561:Cytarabine