Cytotoxic T lymphocyte response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12-transduced tumor cell vaccine

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Abstract
The colon adenocarcinoma C26, carrying two endogenous tumor-associated antigens (TAA) recognized by CTL, has been transduced with the gene coding for the human folate receptor α (FRα) as an additional antigen in order to study the efficacy of vaccination against a tumor expressing multiple antigens. A dicistronic vector was used to transduce the IL-12 genes to create C26/IL-12/FRα that has been used as a cellular vaccine to treat mice bearing lung metastases of C26/FRα. After vaccination mice were partially splenectomized and splenic lymphocytes frozen and used retrospectively to study in vitro CD8 T cell response related to the treatment outcome. Vaccination cured 50% of mice and the effect was CD8 T cell dependent. Mice either cured (responders) or not cured (nonresponders) by vaccination developed tumor-specific CTL. However, analysis of CTL specificity and pCTL frequencies revealed that responders had a predominant CTL activity against endogenous C26- related tumor antigens, whereas nonresponders had CTL that recognized preferentially the FRα antigen. CD8 from responder mice were characterized to release high levels of granulocyte–macrophage (GM)-CSF upon antigen stimulation. Tumors obtained from mice that died despite vaccination lost expression of the FRα transgene but maintained expression of endogenous C26 antigens. Immunoselection against FRα antigen was not observed in tumors from non-vaccinated controls and from CD8-depleted vaccinated mice. Down-regulation of FRα antigen expression was due, at least in part, to methylation of retroviral vector long terminal repeat promoter since FRα expression was partially restored, ex vivo, by treatment with 5-aza-2′-deoxy-cytidine (aza). These results indicate that CD8 T cell-mediated immunoselection and production of GM-CSF are determining factors for the efficacy of tumor vaccines.

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