Yes-Associated Protein 1 Inhibition Induces Immunogenic Cell Death and Synergizes With Radiation and PD-1 Blockade

Purpose Danger signals released by ionizing radiation (IR) can theoretically stimulate immune activation in the tumor environment (TME), but IR alone is not sufficient to induce an effective immune response in clinical practice. In this study, we investigated whether inhibition of yes-associated protein 1 (YAP1) could induce immunogenic cell death (ICD) and whether the combination of YAP1 inhibition with IR could increase in vivo immune infiltration and thereby boost a tumor response to immunotherapy. Methods and Materials First, the expression of ICD markers, markers of T-cell activation, and key proteins involved in innate immune signaling were measured after YAP1 inhibition. Next, the expression level of YAP1 protein was measured after different doses of IR. Then, the antitumor effect of YAP1 inhibition combined with IR was investigated in vivo, and the immune status of the TME was evaluated. Finally, the efficacy of a triple therapy including YAP1 inhibition combined with IR and programmed cell death protein 1 blockade in the treatment of resistant tumors was determined. Results We found that YAP1 inhibition induced ICD and increased the levels of antigen presentation machinery, effectively causing the activation of T cells. Mechanistically, YAP1 inhibition induced cell DNA damage and activated the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Surprisingly, IR upregulated YAP1 expression. IR combined with YAP1 inhibition significantly inhibited cancer growth and prolonged survival, which was related to the augmented infiltration, activation, and function of CD8+ T cells in the TME. Moreover, the addition of YAP1 inhibition significantly improved the efficacy of pancreatic cancer treatment when neither radiation nor programmed cell death protein 1 inhibitors were ideal. Conclusions YAP1 inhibition could trigger ICD and is a potential approach to potentiating the therapeutic efficacy of radiation therapy and anti-PD1 immunotherapy. Danger signals released by ionizing radiation (IR) can theoretically stimulate immune activation in the tumor environment (TME), but IR alone is not sufficient to induce an effective immune response in clinical practice. In this study, we investigated whether inhibition of yes-associated protein 1 (YAP1) could induce immunogenic cell death (ICD) and whether the combination of YAP1 inhibition with IR could increase in vivo immune infiltration and thereby boost a tumor response to immunotherapy. First, the expression of ICD markers, markers of T-cell activation, and key proteins involved in innate immune signaling were measured after YAP1 inhibition. Next, the expression level of YAP1 protein was measured after different doses of IR. Then, the antitumor effect of YAP1 inhibition combined with IR was investigated in vivo, and the immune status of the TME was evaluated. Finally, the efficacy of a triple therapy including YAP1 inhibition combined with IR and programmed cell death protein 1 blockade in the treatment of resistant tumors was determined. We found that YAP1 inhibition induced ICD and increased the levels of antigen presentation machinery, effectively causing the activation of T cells. Mechanistically, YAP1 inhibition induced cell DNA damage and activated the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway. Surprisingly, IR upregulated YAP1 expression. IR combined with YAP1 inhibition significantly inhibited cancer growth and prolonged survival, which was related to the augmented infiltration, activation, and function of CD8+ T cells in the TME. Moreover, the addition of YAP1 inhibition significantly improved the efficacy of pancreatic cancer treatment when neither radiation nor programmed cell death protein 1 inhibitors were ideal. YAP1 inhibition could trigger ICD and is a potential approach to potentiating the therapeutic efficacy of radiation therapy and anti-PD1 immunotherapy.