Chemotherapy broadens the range of tumor antigens seen by cytoxic CD8+ T cells in vivo

C. Jackaman, D. Majewski, Simon Fox, Anna Nowak, D.J. Nelson

    Research output: Contribution to journalArticle

    41 Citations (Scopus)

    Abstract

    Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8+ T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKLCTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNc and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy. © Springer-Verlag 2012.
    Original languageEnglish
    Pages (from-to)2343-2356
    JournalCancer Immunology Immunotherapy
    Volume61
    Issue number12
    DOIs
    Publication statusPublished - 2012

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    Neoplasm Antigens
    Epitopes
    T-Lymphocytes
    Drug Therapy
    Interleukin-2
    gemcitabine
    Cisplatin
    Immune System
    Antigens
    Neoplasms
    Mesothelioma
    Ovalbumin
    Growth
    Tumor Cell Line
    Therapeutics

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    title = "Chemotherapy broadens the range of tumor antigens seen by cytoxic CD8+ T cells in vivo",
    abstract = "Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8+ T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKLCTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNc and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy. {\circledC} Springer-Verlag 2012.",
    author = "C. Jackaman and D. Majewski and Simon Fox and Anna Nowak and D.J. Nelson",
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    Chemotherapy broadens the range of tumor antigens seen by cytoxic CD8+ T cells in vivo. / Jackaman, C.; Majewski, D.; Fox, Simon; Nowak, Anna; Nelson, D.J.

    In: Cancer Immunology Immunotherapy, Vol. 61, No. 12, 2012, p. 2343-2356.

    Research output: Contribution to journalArticle

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    AU - Jackaman, C.

    AU - Majewski, D.

    AU - Fox, Simon

    AU - Nowak, Anna

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    AB - Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8+ T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKLCTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFNc and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy. © Springer-Verlag 2012.

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