Modifying the gastric tumor microenvironment with tadalafil: A transcriptomic analysis of immune signatures from underserved patients of southern Arizona
Abstract
e16104 Background: Gastric adenocarcinoma (GAC) is the fifth most common cancer worldwide with significant morbidity and mortality. Recently, southern Arizona has seen a concerning surge in incidence of GAC due to ineffective H. pylori screening and treatment. Moreover, peri-operative chemotherapy treatment in stage IB-III GAC represents an area of unmet need for new targets. Our center serves a catchment area that is 40% Hispanic and sees a high volume of GAC patients, making this our research focus. Our preclinical work in Helicobacter infected mice showed a subset of myeloid derived suppressor cells (MDSCs) expressing Schlafen4 (SLFN4) concurrently with gastric metaplasia, a GAC precursor. SLFN4+ MDSCs exhibit robust transcriptional signatures associated with type I interferon(IFN-I) inducible genes, coupled with T cell suppressor function. Pharmacological inhibition via phosphodiesterase (PDE) 5,6 inhibitor sildenafil resulted in the suppression of SLFN4, reversal of T cell suppression, and mitigation of metaplasia. This is the first clinical study aimed to characterize SLFN12L, the human ortholog of mouse SLFN4, and to analyze the neoplastic and immune signatures in GAC before and after PDE5 inhibition with tadalafil. Methods: Using single-cell RNA sequencing, we examined tissues from GAC patients enrolled in a "Window of Opportunity" study (NCT05709574). The patients receive tadalafil (20mg) for 14 days, followed by combined tadalafil and FLOT (5-fluorouracil,…
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