PLS-a-GalCer: a novel targeted glycolipid therapy for solid tumors

The prototypical type I natural killer T (NKT) cell agonist, a-galactosylceramide (a-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of a-GalCer currently entails ex vivo priming of patient-derived dendritic cells; however, this technology suffers from cost, logistical concerns, and safety issues. As a parenteral dendritic cell-targeted alternative, we demonstrate that poly(L-lysine succinylated) (PLS)-a-GalCer, a novel scavenger receptor-A1 targeted a-GalCer prodrug has enhanced antitumor activity compared with a-GalCer. To compare the antitumor activity of PLS-a-GalCer and a-GalCer, we used mouse syngeneic subcutaneous pancreatic and cervical tumor models using Panc02 and TC-1 cells, respectively. Intratumoral immune cell infiltration was evaluated using flow cytometry and immunohistochemistry whole-slide scan analysis. Serum cytokine levels were examined by ELISA and LEGENDplex analysis. Type I NKT cell intracellular interferon-gamma (IFN-?) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-a-GalCer and a-GalCer in antigen-presenting cells (APCs). The scavenger receptor A1 (SR-A1)-mediated targeting of a-GalCer to APCs by PLS-a-GalCer significantly improves the antitumor function against solid tumors compared with a-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-a-GalCer increases intratumoral antigen-specific T, NKT and T cells, and increases the M1/M2 macrophage ratio. In the TC-1 tumor model, we demonstrated that PLS-a-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-a-GalCer is dependent on type I NKT cells and requires SR-A1 targeting. In addition, using SR-A1 knockout RAW cells, a murine macrophage cell line, we showed that PLS-a-GalCer uptake and processing in APCs are more efficient compared with a-GalCer. PLS-a-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-? for a longer period and increases Th1:Th2 cytokine ratios compared with a-GalCer. PLS-a-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with a-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors. © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.

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