Work

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

Year: 2025

Type: article

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)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1344