Search

iNKT cells – often referred as the “Swiss Army knife” of the immune system – have emerged as central players in cancer vaccine therapies. Glycolipids activating iNKT cells, such as α-galactosylceramide (αGalCer), can enhance the immune response against co-delivered cancer antigens and have been applied in the design of self-adjuvanting anti-tumor vaccines. In this context, this work focuses on the chemical synthesis of ganglioside tumor-associated carbohydrate antigens (TACAs), namely GM3 and (Neu5Gc)GM3 antigens, their conjugation to αGalCer, and their formulation into liposomes as an efficient platform for their in vivodelivery. Liposomes containing GM3–αGalCer, (Neu5Gc)GM3–αGalCer, and equimolar amounts of the two conjugates have been fully characterized and their ability to activate iNKT cell has been confirmed ex vivoin mouse and human cell assays. The candidates were tested in in vivoimmunization studies, demonstrating an ability to induce both TH1 and TH2 cytokines leading to the production of all subclasses of IgG antibodies. Notably, the study also demonstrated that serum antibodies raised against the two TACAs, alone and in combination, were cross-reactive. This finding has consequences for future vaccine designs – even if a highly tumor-selective antigen is chosen, the resulting antibody response may be broader than anticipated.

Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.