Abstract

Immune responses are strongly regulated by different co-stimulatory and co-inhibitory molecules, which allow the immune system to distinguish between physiological cells and malignant cells, recognised as “foreign”. A hallmark of cancer cells is to avoid detection by the immune system, and tumours evade immune responses by exploiting immune checkpoint pathways.
In recent years, a growing understanding of the biology of immune checkpoints and tumour immune evasion mechanisms has led to the development of immune checkpoint inhibitors in the form of monoclonal antibodies, designed to target co-stimulatory and co-inhibitory molecules in order to re-engage the immune system and restore anti-tumour immune responses. Despite this advance, many cancers still escape the immune system detection and fail to respond to the immune therapy. On top of this, as all immune checkpoint inhibitors explored so far fall in the category of monoclonal antibodies, therapy with these agents is associated with very high costs, longer response times in comparison with standard chemotherapy and several systemic side-effects.
Immune checkpoint therapy has dramatically changed the efficacy of anti-cancer treatment and the exploration of novel immunological targets, along with the design of new small-molecule modulators of these pathways, constitutes a global research priority and an innovative research field.
Searching for new immune checkpoint modulators, we are focussing our efforts on three different immune checkpoint proteins and their ligands: CTLA-4:B7-1/B7-2, PD-1:PD-L1 and CD200:CD220R. Using molecular modelling techniques, we have performed a series of virtual screenings of different libraries of commercial compounds (~3 millions), in order to identify novel small-molecules able to block these immune checkpoint proteins by disrupting their interactions with the ligands. The molecules selected in silico have been evaluated for their ability to block immune checkpoint protein-ligand interactions, to re-engage the immune system and restore anti-tumour immune responses using different biochemical and cell-based assays.