title: Induction of unresponsiveness limits tumor protection by adoptively transferred MDM2-specific cytotoxic T lymphocytes.
abstract: There is evidence showing that high avidity CTLs can be more effective than low avidity CTLs for adoptive tumor immunotherapy. Because many T cell-recognized tumor antigens are nonmutated self-proteins, tolerance mechanisms are likely to render high avidity T cells unresponsive or cause T cell elimination by clonal deletion. We recently used the allo-restricted strategy to circumvent immunologic tolerance to a ubiquitously expressed tumor-associated protein, MDM2, and raised high avidity CTLs in humans and in mice. In this study, we investigated whether high avidity MDM2-specific CTLs can mediate tumor protection without causing damage to normal tissues in mice. Although the CTLs prolonged survival of tumor-bearing mice without causing damage to normal tissues, tumor protection was incomplete. We show that tumor growth occurred despite the continued presence of MDM2-specific CTLs and the continued susceptibility of tumor cells to CTL killing. However, analysis of the CTLs revealed that they had been rendered unresponsive in vivo because they did not produce interferon gamma in response to antigen-specific stimulation. These experiments suggest that induction of unresponsiveness may be an important mechanism limiting the efficacy of adoptive CTL therapy.
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Gavin M
authors.initials: GM
authors.lastname: Bendle
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.forename: Luke-Kwok
authors.initials: LK
authors.lastname: Pang
authors.forename: Stephen
authors.initials: S
authors.lastname: Hsu
authors.forename: Mauro
authors.initials: M
authors.lastname: Krampera
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D009687:Nuclear Proteins / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D051736:Proto-Oncogene Proteins c-mdm2; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D007371:Interferon-gamma; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2