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    CD8+ cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy

    Access Status
    Fulltext not available
    Authors
    Jackaman, Connie
    Gardner, J.
    Tomay, F.
    Spowart, J.
    Crabb, Hannah
    Dye, Danielle
    Fox, Simon
    Proksch, Stephen
    Metharom, Pat
    Dhaliwal, S.
    Nelson, Delia
    Date
    2019
    Type
    Journal Article
    
    Metadata
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    Citation
    Jackaman, C. and Gardner, J. and Tomay, F. and Spowart, J. and Crabb, H. and Dye, D. and Fox, S. et al. 2019. CD8+ cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy. OncoImmunology.
    Source Title
    OncoImmunology
    DOI
    10.1080/2162402X.2018.1564452
    ISSN
    2162-4011
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/74358
    Collection
    • Curtin Research Publications
    Abstract

    © 2019, © 2019 The Author(s). Published with license by Taylor & Francis Group, LLC. Increasing life expectancy is associated with increased cancer incidence, yet the effect of cancer and anti-cancer treatment on elderly patients and their immune systems is not well understood. Declining T cell function with aging in response to infection and vaccination is well documented, however little is known about aged T cell responses to tumor antigens during cancer progression or how these responses are modulated by standard chemotherapy. We examined T cell responses to cancer in aged mice using AE17sOVA mesothelioma in which ovalbumin (OVA) becomes a ‘spy’ tumor antigen containing one dominant (SIINFEKL) and two subdominant (KVVRFDKL and NAIVFKGL) epitopes. Faster progressing tumors in elderly (22–24 months, cf. 60–70 human years) relative to young (2–3 months, human 15–18 years) mice were associated with increased pro-inflammatory cytokines and worsened cancer cachexia. Pentamer staining and an in-vivo cytotoxic T lymphocyte (CTL) assay showed that whilst elderly mice generated a greater number of CD8+ T cells recognizing all epitopes, they exhibited a profound loss of function in their ability to lyse targets expressing the dominant, but not subdominant, epitopes compared to young mice. Chemotherapy was less effective and more toxic in elderly mice however, similar to young mice, chemotherapy expanded CTLs recognizing at least one subdominant epitope in tumors and draining lymph nodes, yet treatment efficacy still required CD8+ T cells. Given the significant dysfunction associated with elderly CTLs recognizing dominant epitopes, our data suggest that responses to subdominant tumor epitopes may become important when elderly hosts with cancer are treated with chemotherapy.

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