TP4 - InCa

STING pathway activation and cancer-associated inflammation

The discovery and development of immunotherapy using programmed death-1 (PD-1) or its ligand (PD-L1) blockade has revolutionized cancer therapy in recent years. Despite therapeutic successes that have never been observed before, these are only recorded in about 20% of solid tumor entities with pre-existing immune activation. In the vast majority of cases, lung cancer is caused by long-term smoking and is therefore characterized by the occurrence of a high mutation rate in the tumours. This in turn can be a positive indication for immunotherapy. However, it has been shown that only 12% of patients with non-small cell lung cancer (NSCLC) treated with immunotherapy survive two years without progression, a finding that suggests the rapid development of resistance. Several studies have recently shown that inactivation of interferon (IFN)- signaling pathway genes plays a role in acquired resistance to immunotherapy. Interestingly, work has also shown that the stimulator of interferon genes (STING) signaling pathway is spontaneously activated in cancer due to cytosolic DNA favored by chromosomal instability. These data suggest that lung tumor cells with chromosomal instability and a consequent high mutation rate may be subject to activation of type I and type II IFN signaling, which may be induced by T cells but also in a cancer cell autonomous manner. Notably, virally induced STING activation can induce necroptosis, an inflammatory type of necrotic cell death that has been shown to stimulate antitumor immunity. STING-induced interferon signaling induces the expression of Z-DNA-binding protein 1 (ZBP1), which can trigger virus-induced necroptosis. In this regard, we have shown that ZBP1 induces necroptosis and skin inflammation in mice with epidermal RIPK1 knockout (Lin et al. Nature, 2007). Therefore, our goal is to understand the role of the STING signaling pathway and ZBP1 as a downstream effector of necroptosis in lung tumor development, to induce anti-tumor immunity through targeted activation of necroptosis, and to use this as a therapeutic strategy in initially preclinical models for NSCLC testing.