Abstract 7298: DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma
Authors: Brian J. Thomas, Xue Bai, Benjamin J. Cryer, Mark A. Daniels, Margaret J. Lange, Donald H. Burke
Journal: Cancer Research (2025)

Abstract The major success of immune checkpoint inhibitors (ICIs) to treat cancer highlights both the efficacy of inhibiting immunosuppressive proteins as a means of re-activating the anti-tumor immune response and the generalizability of targeting such proteins (i.e., therapies are clinically useful across many cancer types). While the major focus in immuno-oncology has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or enhance adaptive responses. In this work we detail the intracellular protein, Dual Specificity Phosphatase 11 (DUSP11), as an innate immune checkpoint (iIC) in lung adenocarcinoma (LUAD), among other cancers. LUAD remains a leading cause of death worldwide, largely due to mutant oncogene acquired therapeutic resistance and a lack of effective alternative therapeutic options, including ICIs. There is a clear unmet need for new methods to treat refractory LUAD. In this work we targeted DUSP11, a phosphatase with high affinity for 5’ triphosphate RNA (3pRNA) that has readily been reported as a host factor that aids viruses escape of immune detection. As many cancers show dysregulated RNA transcript processing, we hypothesized that DUSP11 knockdown would increase the presence and detection of immunostimulatory RNA by pattern recognition receptors (PRRs) and activate anti-cancer immune mechanisms. To do this, we engineered multiple Dicer substrate small interfering RNAs targeting DUSP11 and showed that decreased expression at the mRNA and protein levels had significant impacts on cell viability for multiple cancer cell types, including LUAD. The decrease in LUAD cell viability was due to induction of apoptosis, and innate immune responses were significantly upregulated, evidenced by increased expression of interferon-stimulated genes (ISGs), release of type I IFN, and paracrine stimulation of cells expressing IFNAR1. As retinoic acid inducible gene I (RIG-I) was an ISG that was upregulated upon DUSP11 knockdown, we speculated that, as in viral studies, RIG-I was responsible for the anti-cancer phenotype. Indeed, the knockdown of RIG-I, but not other intracellular PRRs, recovered the cell viability and innate immune response phenotypes. To corroborate this, we showed that knocking down DUSP11 enhances the effect of RIG-I agonizing 3pRNA, and we showed that LUAD cells engineered to be deficient in RIG-I do not respond to DUSP11 knockdown. Ongoing studies in mice appear to show that the anti-cancer effect of modulating DUSP11 activity is conserved in vivo. Overall, our preclinical studies suggest that DUSP11 is an excellent target to modulate innate immunity and induce LUAD cell death. Early studies suggest that this target and mechanism is generalizable to other cancer types; however, understanding which cancers respond and why, as well as assessing the safety and toxicity of targeting this protein warrant further investigation. Citation Format: Brian J. Thomas, Xue Bai, Benjamin J. Cryer, Mark A. Daniels, Margaret J. Lange, Donald H. Burke. DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7298.