Targeting dendritic cells to improve antitumor immunity

Despite the major success and recent advances in therapies treating cancer, including ICI and cancer vaccines, these agents often fail to induce durable responses or complete remissions in the majority of patients. One of the reasons may be the poor network linking innate and adaptive immunity. In this thesis, we focus on targeting the innate immune system, particularly DCs, as recent evidence has highlighted the fundamental role of these cells in orchestrating cancer immunity. First, I described how chemotherapeutics, particularly microtubule-destabilizing agents, initially designed to target the proliferation or induce cell death of malignant cells, also induce direct DC maturation through GEF-H1. Second, I present a work where we used an ASO-based technology with the dual capacity of trigger DC activation via TLR9 engagement and control of PD-L1 in mice to overcome the limited therapeutic efficacy of anti-PD-L1 mAb. This work provides a mechanistic groundwork for future therapy design and shows how activating intratumoral DCs with chemotherapy or immunomodulatory ASOs improve antitumor immunity, having even greater efficacy when combined with other ICIs for the treatment of solid tumors.