Targeting phosphodiesterase 10 unleashes antitumor immunity by inhibiting the RAS-MAPK signaling in cancer cells and myeloid-derived suppressor cells 3553

Abstract Description Previous studies reported that the cyclic nucleotide degrading enzyme, phosphodiesterase 10A (PDE10) is overexpressed in various cancer tissues and essential for cancer cell proliferation and survival. ADT-030 is a novel PDE10 inhibitor by screening a focused library of indenes for PDE10 inhibitory activity. Here, we report that ADT-030 oral administration resulted in robust tumor growth control in multiple mouse tumor models. The antitumor activity of ADT-030 was diminished in immunodeficient mice or mice depleted of CD8+ T cells, suggesting the dependence of ADT-030 on host immunity. The combination of ADT-030 and anti-PD-1 immune checkpoint inhibition therapy led to further improved animal survival in two mouse colon cancer models. Comprehensive immune profiling by CyTOF and single-cell RNA-seq (scRNAseq) analyses revealed marked reduction of MDSCs and restoration of T cells, B cells and NK cells in the tumor microenvironment after ADT-030 treatment. Mechanistically, ADT-030 selectively reduced RAS-MAPK signaling in tumor cells and MDSCs, accompanied by p53 activation and induction of apoptosis in these cells. Moreover, ADT030-induced immunogenic cell death in cancer cells promoted dendritic cell antigen uptake and maturation. Altogether, our study provides insight into the mechanism of action of ADT-030 and underscores the potential of ADT-030 as a monotherapy or in combination with immunotherapies for treating cancers with mutant or activated RAS. Funding Sources CA238514, CA264983, CA215523 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)