CCL3/MIP-1 α Is a Potent Immunostimulator When Coexpressed with Interleukin-2 or Granulocyte-Macrophage Colony-Stimulating Factor in a Leukemia/Lymphoma Vaccine

Abstract

Chemokines orchestrate trafficking of immune effector cells during inflammation. Here we demonstrate that chemokines also serve to potentiate effector cell-mediated antineoplastic immune responses in vaccination strategies. As a critical mediator of inflammation, macrophage inflammatory protein 1α (CCL3/MIP-1α) attracts and stimulates both antigen-presenting and cytotoxic cells. In the A20 leukemia/lymphoma vaccine model, we explored the efficacy of MIP-1α in combination with interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF). After subcutaneous injection of the MIP-1α + IL-2 or MIP-1α + GM-CSF combination vaccine, focal but pronounced infiltrates of CD4⁺ and CD8⁺ T cells were observed at the vaccination sites. In mice with preestablished leukemia/lymphoma, survival is significantly improved in animals treated with MIP-1α + GM-CSF- and MIP-1α + IL-2-secreting vaccines. Protection is superior in the MIP-1α + GM-CSF group, with the effects of MIP-1α and GM-CSF being synergistic. In contrast, suppression of lymphoblast proliferation by single-immunogen vaccines secreting MIP-1α, GM-CSF, or IL-2 alone does not translate to improved survival. The systemic protective effects afforded by the MIP-1α + IL-2 or MIP-1α + GM-CSF combination are mediated by different effector cell populations. In the MIP-1α + IL-2 group, antineoplastic defense is mediated by CD8⁺ T and NK cells, whereas in the MIP-1α + GM-CSF group CD4⁺ T cells are involved in addition to CD8⁺ cytotoxic T cells, underscoring that T cell help is critical for long-term protection. Thus combination of MIP-1α with different cytokines recruits different sets of effector cells into a potent antineoplastic immune response.