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.
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 ...
CMV drives the expansion of highly functional memory T cells expressing NK-cell receptors in renal transplant recipientsMakwana, N.; Foley, B.; Fernandez, S.; Lee, S.; Irish, A.; Pircher, H.; Price, Patricia (2017)Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post-transplant. We describe how active and latent CMV affect ...