Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ - independent resolution of treated-turmors and CD4+ -dependent systemic and memory responses
MetadataShow full item record
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.
Showing items related by title, author, creator and subject.
Murine mesothelioma induces locally-proliferating IL-10<sup>+</sup>TNF-a<sup>+</sup>CD206<sup>-</sup>CX3CR1<sup>+</sup> M3 macrophages that can be selectively depleted by chemotherapy or immunotherapyJackaman, Connie; Yeoh, T.; Acuil, M.; Gardner, Joanne; Nelson, Delia (2016)© 2016 Taylor & Francis Group, LLC.We used a murine model to monitor changes to myeloid cell subsets, i.e., myeloid-derived suppressor cells (MDSCs), M1 macrophages that secrete pro-inflammatory cytokines and express CD40 ...
Jackaman, Connie; Radley-Crabb, Hannah; Soffe, Z.; Shavlakadze, T.; Grounds, M.; Nelson, Delia (2013)Changes to innate cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), during aging in healthy or tumor-bearing hosts are not well understood. We compared macrophage subpopulations and MDSCs from healthy ...
Gardner, J.; Mamotte, Cyril; Patel, P.; Yeoh, T.; Jackaman, Connie; Nelson, Delia (2015)Dendritic cells (DCs) play an important role in the generation of anti-cancer immune responses, however there is evidence that DCs in cancer patients are dysfunctional. Lipid accumulation driven by tumor-derived factors ...