Abstract
Development of simple and fully characterized immunomodulatory molecules is an active area of research to enhance current immunotherapies. Monophosphoryl lipid A (MPL), a nontoxic lipidic derivative from bacteria, is the first and currently only adjuvant approved in humans. However, its capacity to induce a potent response against weak immunogenic tumoral‐associated antigens remains limited. Herein, a new generation of lipidic immunomodulators to conduct a structure–activity relationship study to determine the minimal structural elements conferring immunomodulatory properties is introduced. Two lead molecules characterized by a short succinyl linker between two oleyl chains and a polar headgroup consisting of either naturally occurring tobramycin (DOST) or kanamycin (DOSK) are identified. These two lipoaminoglycosides self‐assemble in very small vesicles. In a wide variety of cells including 3D human cell culture, DOST and DOSK induce the upregulation of proinflammatory cytokines and interferon‐inducible proteins in a dose and time‐dependent manner via a caveolae‐dependent proinflammatory mechanism and phosphatidylinositol phospholipase C activation. Furthermore, after intratumoral administration, these lipoaminoglycosides induce an efficient immune response leading to significant antitumor activity in a mouse breast cancer model. Altogether, these findings indicate that DOST and DOSK are two groundbreaking synthetic lipid immunostimulators that can be used as adjuvants to enhance current immunotherapeutic treatments.
Highlights
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The treatment of C2C12 cells with DOSP or DOSN only led to a slight overexpression of interferon β1 (IFNβ1), interleukin 6 (IL-6), CXCL10, dependent activator of interferon regulatory factors (DAI), and interferongamma induced protein 204 (IFI204) compared to untreated cells (Figure 1b)
DOST and DOSK treatment enhanced by 50- to 500-fold the expression of IFNβ1, CXCL10, and DAI, and most importantly, they induced a significant increase of IL-6 and IFI204 expression
Summary
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. A new generation of lipidic immunomodulators to conduct a structure–activity relationship study to ment has recently been the focus of much research aimed at preventing tumor cells from evading immune attack. This lead to the emergence of checkpoint inhibitors, including antiprogrammed death protein 1 (PD-1) or anti-PD ligand 1 (PD-L1). Two lead molecules characterized by a short succinyl linker between two oleyl chains and a polar headgroup consisting of either naturally occurring tobramycin (DOST) or kanamycin (DOSK) are identified These two lipoaminoglycosides self-assemble in very small vesicles. These findings indicate that DOST and DOSK are two groundbreaking synthetic lipid immunostimulators that can be used as adjuvants to enhance current immunotherapeutic treatments
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