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, leucovorin, oxaliplatin, and docetaxel) for 8 weeks. Gastric tissue and blood samples were collected i) before treatment, ii) after 14 days of tadalafil, and iii) after 8 weeks of combined treatment. We have enrolled 3 Hispanic patients to date with ongoing enrollment. Results: Tumors exhibited responses as per radiologic and pathologic criteria. In contrast to SLFN4, primarily expressed in myeloid cells, SLFN12L was found in most CD14+T lymphocytes and natural killer cells. A prominently activated and expanded myeloid population expressing SLFN12L was identified in the gastric mucosa of GAC patients. These cells exhibited transcriptional signatures associated with IFN-I signaling and immunosuppressive activities, diminishing after tadalafil treatment. Within GAC tissue, a notable increase in exhausted T cells and regulatory T cells was observed, decreasing after tadalafil. Post-tadalafil testing showed tissue PDE5/6 inhibition and higher plasma cGMP. Effector T cells exhibited an upward trend following tadalafil, suggesting a reduction in tumor immunosuppression. Conclusions: Preliminary data of this ongoing study show that tadalafil treatment combined with FLOT, has the potential to decrease SLFN12L+ MDSC, to attenuate their immunosuppression, and potentially inhibit tumor progression. The trial is active and further analysis will be presented in due course.