Elucidating the mechanisms of paclitaxel-loaded-nanoparticle-induced immune response

Dentritic cells (DC) are the most potent antigen-presenting cells and play a key role in the induction of effective immune responses, suggesting a novel target for anti-tumor immunotherapy. Paclitaxel (PXL) is a widely used chemotherapeutic, initially characterized as a mitotic inhibitor, that has been shown to enhance maturation and function of DCs as well as up-regulate the production of inflammatory cytokines. Thus, modulation of DC function by the approved-for-human-use PXL could constitute a novel approach for reshaping immune responses against a tumor. For targeted delivery of PXL to DCs in the lymph nodes (LNs), where they are present in high concentrations and apt for antigen uptake, poly(propylene) sulfide core nanopatricles (NPs) developed by our laboratory have been used. PXL loaded-NP (PXL-NP) treatment induces massive immune cell infiltration into the draining LN 24h after intradermal injection of PXL-NPs in mice, suggesting that PXL-NP treatment induces a local and robust immune response (Thomas et al., in preparation). We hypothesized that this effect stems directly from the action of PXL-NPs on LN-resident DCs. We demonstrate that PXL-NPs are able to induce maturation and cytokine production in murine and human DCs in vitro, which may explain the in vivo observations of robust cell recruitment to the draining LN and generation of adaptive immune responses. Furthermore, the striking cell infiltration in the LN upon PXL-NP treatment was abrogated in complement protein 3 (C3) knockout mice in vivo (Thomas et al. in preparation). Interestingly, we show that the presence of C3 regulates IL-12p40 expression and, in turn, plays a crucial role in the activation of mature, functional DCs in response to PXL-NPs. Thus, the absence of functional DCs in case of C3 deficiency might account for the hindered infiltration. Together, this data suggests that PXL-NPs may effectively direct the immunomodulatory action of PXL to LN-resident DCs to alter immune responses.