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    Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ - independent resolution of treated-turmors and CD4+ -dependent systemic and memory responses

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    Authors
    Jackaman, Connie
    Nelson, Delia
    Date
    2012
    Type
    Journal Article
    
    Metadata
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    Citation
    Jackaman, C. and Nelson, D. 2012. Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ - independent resolution of treated-turmors and CD4+ -dependent systemic and memory responses. Cancer Immunology, Immunotherapy. 61: pp. 549-560.
    Source Title
    Cancer Immunology, Immunotherapy
    Additional URLs
    http://link.springer.de/link/service/journals/00262/index.htm
    ISSN
    0340-7004
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/49275
    Collection
    • Curtin Research Publications
    Abstract

    Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4? and CD8? T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumorspecific CD8? T cells did not upregulate CD44. A twotumor model showed that while IL-2-treated-site tumors resolved, distal tumors continued to grow, implying limited systemic immunity. In contrast, anti-CD40 Ab treatment with or without IL-2 expanded the systemic T cell response to non-draining lymph nodes, and distal tumors resolved. Tumor-specific T cells in lymph nodes of anti-CD40 Ab ± IL-2-treated mice upregulated CD44, demonstrating activation and transition to effector/memory migratory cells. While CD40-activated CD4? T cells were not required for eradicating treated-site tumors, they, plus CD8? T cells, were crucial for removing distal tumors. Rechallenge/depletion experiments showed that the effector/memory phase required the presence of previously CD40/IL-2-activated CD4? and CD8? T cells to prevent recurrence. These novel findings show that different T cell effector mechanisms can operate for the eradication of local treated-site tumors versus untreated distal tumors and that signaling through CD40 generates a whole of body, effector/memory CD4? and CD8? T cell response that is amplified and prolonged via IL-2. Thus, successful immunotherapy needs to generate collaborating CD4? and CD8? T cells for a complete long-term protective cure.

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