Nanoparticle-based Therapeutic Intervention of cAMP-mediated Immunosuppression in Malignant Melanoma
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Abstract
Malignant melanoma is a form of skin cancer which, even though it represents its least prevalent form, is accountable for 90% of skin cancer related deaths. While treatment of malignant melanoma up until Stage III promises great success, the same so far does not apply to Stage IV melanoma patients. In recent years, the introduction of novel treatment regiments has raised patients hopes for survival, but limited treatment success requires further development and combination of current and novel strategies.
Modifications in metabolic pathways such as the accumulation of the intracellular second messenger cyclic adenosine monophosphate (cAMP) have been recognized as a hallmark of cancer. In melanoma, elevated intracellular cAMP levels correlate with a greater metastatic potential and are believed to be the cause of regulatory T cell (Treg)-mediated immunosuppression in the tumour. In the present study, it was investigated how a micellar formulation of the adenylyl cylase inhibitor MDL-12, 330A hydrochloride made from the amphiphilic polypeptoid-block-polypeptide copolymer polysacrcosine-block-polyglutamatic acid benzylester (PSar-b-PGlu(OBn)) can be used to intervene in the formation of cAMP.
The in vivo testing of cAMP reduction using the adenylyl cyclase inhibitor MDL-12, 330A hydrochloride showcased its potential as a therapeutic agent by significantly reducing the tumour burden in the context of the murine B16F10-OVA melanoma model. A detailed examination of the tumour immune cell infiltrate following cAMP reduction revealed drastic quantitative and functional changes. Based on these results, a treatment strategy for complete tumour rejection was successfully established, combining cAMP reduction with punctual Treg removal.
In addition, the potential of azide functionalized polysarcosine brushes with polylysine backbone and polysarcosine side chains labelled with the fluorescent dye Alexa Fluor 647 and coupled with antigen and adjuvant could be demonstrated as a protective and therapeutic cancer vaccine. In order to completely eliminate tumour growth in a therapeutic approach, it would be interesting to try to combine it with cAMP reduction.