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

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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 tumor-specific CD8+ T cells did not upregulate CD44. A two-tumor 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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Abbreviations

Ab:

Antibody

i.t.:

Intratumoral

dLN:

Draining lymph node

non-dLN:

Non-draining lymph node

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Acknowledgments

This work was supported by the Cancer Council of WA, the Mesothelioma Applied Research Foundation (MARF), and the Australian Lung Foundation (ALF).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. School of Biomedical Sciences, Immunology and Cancer Group, Curtin University, Kent St., Bentley, Perth, WA, 6102, Australia

    Connie Jackaman & Delia J. Nelson

  2. Western Australia Biomedical Research Institute, Bentley, Perth, WA, 6102, Australia

    Connie Jackaman & Delia J. Nelson

  3. Curtin Health Innovation Research Institute, Bentley, Perth, WA, 6102, Australia

    Connie Jackaman & Delia J. Nelson

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  1. Connie Jackaman
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  2. Delia J. Nelson
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Correspondence to Delia J. Nelson.

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Jackaman, C., Nelson, D.J. Intratumoral interleukin-2/agonist CD40 antibody drives CD4+-independent resolution of treated-tumors and CD4+-dependent systemic and memory responses. Cancer Immunol Immunother 61, 549–560 (2012). https://doi.org/10.1007/s00262-011-1120-5

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  • DOI: https://doi.org/10.1007/s00262-011-1120-5

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