Advancing immunotherapies by exploiting novel pathways controlling dendritic cell differentiation

In recent years, the landscape of cancer therapy has shifted dramatically. Novel approaches based on harnessing the patient’s own immune system have revolutionized the treatment scheme and are evolving as promising strategies to not only manage but also cure cancer patients. Immunotherapy marks an entirely different way of treating cancer by targeting the immune system, not the tumour itself. Bolstering the function of T cells infiltrating the tumour has been a primarily focus of such immunotherapies. Yet most cancer patients harbor tumours that lack or have limited T cell infiltrates (“cold tumours”). Treating these “cold tumours” represents a major challenge for current immunotherapy protocols. Therefore innovative strategies, aimed at increasing tumour immunogenicity are urgently needed. Dendritic cells (DCs) represent a particularly attractive therapeutic target, as they are endowed with the unique potential to take up tumor-associated antigens (TAAs) and prime T cells, as well as to orchestrate their expansion, functional polarization and effector activity in lymphoid and non-lymphoid tissues. These natural adjuvant properties make DCs particularly well suited for cell-based therapies. Clinical trials to date have overwhelmingly used DCs that were derived from the ex-vivo differentiation of monocytes into so-called moDCs, as their manufacturing process is straightforward and efficient. Yet, immunotherapies using moDCs have shown limited efficacy in part due to their limited cytokine release, their poor homing properties to the lymph nodes and propensity to develop immunosuppressive functions. In contrast to moDCs, conventional (c)DCs are thought to be the physiological regulators of adaptive immune responses. Mounting evidence suggests that type 1 cDCs (cDC1s) play an integral role in tumour immunity and represent an exciting alternate cell type for vaccination purposes. Yet our understanding of the mechanisms controlling the differentiation of cDC subsets is lacking and has critically hindered their study and translational applications. Recently we discovered a critical role for the poorly characterized transcription factor DC-SCRIPT (encoded by Zfp366) in controlling cDC1 differentiation. Using loss and gain of function approaches we found that DC-SCRIPT exerted a key role in the production of essential cellular factors, such as IL-12, that act to license CD8 T cells for tumour killing. In light of these findings, we hypothesise that DC-SCRIPT is a critical regulator of DC fate choice and immunogenicity and is thus a potential target for approaches to modulate the make-up of DC subsets for therapeutic benefit.