Molecular mechanism and inhibition of extracellular vesicle-mediated PD-L1 release in melanoma cells

ended

Harnessing the power of the immune system to treat cancer has long been a sought after goal of oncological research. Immune checkpoint inhibitors, such as anti-programmed death receptor 1 (PD-1) blockade therapies, have now taken center stage. However not all patients respond, highlighting gaps in our understanding of the mechanisms of tumour immunosuppression. Upregulation of the PD-1 ligand (PD-L1) on tumour cells initiated this therapeutic direction, yet it is becoming clear that the modality of PD-L1-mediated immune suppression is not limited to the plasma membrane. Like many tumor cells, melanoma cells secrete small extracellular vesicles (EVs) with pro-tumorigenic properties. Melanoma EVs express PD-L1 that suppress T cell function and facilitate tumour growth in pre-clinical mouse models. This systemic mechanism is clinically relevant, as circulating EV-PD-L1 levels can stratify anti-PD-1 clinical responders from non-responders. Thus inhibiting EV-PD-L1 may increase anti-PD-1 efficacy and broaden the responder bracket. One plausible strategy would be to block tumor EV secretion, yet little is known about the molecular mechanisms that drive PD-L1 loading and release. Herein, I intend to uncover the molecular mechanisms of EV PD-L1 release from melanoma cells using state-of-the-art optical and bioluminescent reporters to reveal novel druggable targets. This basic knowledge will be exploited to guide subsequent inhibition, through a drug screen for candidates that inhibit EV-PD-L1 release and restore T cell function. Ideally the outcome of this in vitro study will provide a strong rationale for combining anti-PD-1 agents with inhibitors of EV-PD-L1 secretion, to be tested in pre-clinical mouse models. If successful, melanoma EV blockade may remove the unanticipated bottlenecks that surround the efficacy of anti-PD-1 therapy. In the long term this study is meant to lay groundwork for tumor EV inhibition as a therapeutic strategy for cancer types beyond melanoma.