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

被引:0
作者
Burks, Julian [1 ]
Tiwary, Shweta [1 ]
Stevens, David M. [2 ]
Skoczen, Sarah L. [2 ]
Kularatne, Ruvanthi N. [2 ]
Stern, Stephan T. [2 ]
Berzofsky, Jay A. [1 ]
机构
[1] NCI, Ctr Canc Res, Vaccine Branch, Bethesda, MD 20892 USA
[2] NCI, Leidos Biomed Res Inc, Canc Res Technol Program, Nanotechnol Characterizat Lab,Frederick Natl Lab C, Frederick, MD USA
关键词
Tumor microenvironment - TME; Immunotherapy; NKT Cells; Scavenger Receptor; Galactosylceramides; KILLER T-CELLS; NKT CELLS; PHASE-I; SCAVENGER RECEPTOR; GALACTOSYLCERAMIDE; IMMUNITY; ACTIVATION; ANERGY; CANCER; MACROPHAGES;
D O I
10.1136/jitc-2024-009539
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background The prototypical type I natural killer T (NKT) cell agonist, alpha-galactosylceramide (alpha-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of alpha-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)-alpha-GalCer, a novel scavenger receptor-A1 targeted alpha-GalCer prodrug has enhanced antitumor activity compared with alpha-GalCer.Methods To compare the antitumor activity of PLS-alpha-GalCer and alpha-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-gamma) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-alpha-GalCer and alpha-GalCer in antigen-presenting cells (APCs).Results The scavenger receptor A1 (SR-A1)-mediated targeting of alpha-GalCer to APCs by PLS-alpha-GalCer significantly improves the antitumor function against solid tumors compared with alpha-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-alpha-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-alpha-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-alpha-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-alpha-GalCer uptake and processing in APCs are more efficient compared with alpha-GalCer. PLS-alpha-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-gamma for a longer period and increases Th1:Th2 cytokine ratios compared with alpha-GalCer.Conclusions PLS-alpha-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with alpha-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors.
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页数:13
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