title: Synergistic antitumor effects of regulatory T cell blockade combined with pemetrexed in murine malignant mesothelioma.
abstract: CD4(+)CD25(+) regulatory T cells (Tregs) can promote the growth of some tumors, but it is unknown whether this is true for all tumors, including malignant pleural mesothelioma. We have previously shown that the existence of Tregs was associated with poor survival in patients with malignant pleural mesothelioma. In this study, using an intrathoracic murine model of malignant mesothelioma (MM), we provide evidence suggesting that Treg blockade could enhance survival when combined with pemetrexed in established tumor. AC29 murine MM cells were injected into the right pleural cavity of CBA mice for tumor development. Four days after the tumor injection, tumor-bearing mice were then treated with pemetrexed alone, Treg blockade alone, or a combination of pemetrexed and Treg blockade. We observed a synergistic antitumor effect of Treg blockade combined with pemetrexed resulting in prolonged survival. The combination of Treg blockade and pemetrexed was associated with decreased tumor-infiltrating Tregs, increased IL-2 production, dendritic cell maturation, and increased CD3(+)CD8(+)IFN-gamma(+) tumor-infiltrating T cells when compared with mice treated with pemetrexed alone or Treg blockade alone. The survival benefit was abrogated if anti-CD8 mAb was administered simultaneously. Likewise, the survival benefit resulting from the combined Treg blockade with pemetrexed was not observed when immunodeficient mice were used. Therefore, this study suggests that Treg blockade combined with pemetrexed can suppress mesothelioma growth in established tumor in vivo through an immune-mediated process. This study also validates a new intrathoracic tumor model of pleural effusion to explore the role of antitumor immunity in murine MM.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, University Health Network, University of Toronto, Ontario, Canada.
authors.forename: Masaki
authors.initials: M
authors.lastname: Anraku
authors.forename: Tetsuzo
authors.initials: T
authors.lastname: Tagawa
authors.forename: Licun
authors.initials: L
authors.lastname: Wu
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yun
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnston
authors.forename: Marc
authors.initials: M
authors.lastname: de Perrot
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D005971:Glutamates; D053645:Interleukin-2 Receptor alpha Subunit; D000068437:Pemetrexed; D006147:Guanine