Abstract LB104: Preclinical evaluation of the role of Galectin-1 in tumor immune evasion associated mechanisms using a highly selective Galectin-1 small molecule inhibitor

Abstract

Abstract Galectin-1 (Gal-1) is a β-galactoside-binding lectin that is highly expressed within the tumor microenvironment (TME) of some aggressive cancers and whose high expression correlates strongly with poor survival. Following a data mining exercise of external publication data and additional clinical biomarker datasets, we found strong evidence concluding the potential role of Gal-1 in the establishment of a fibrotic tumor stroma and mechanisms associated with tumor invasion, metastasis and angiogenesis. However, there was limited data regarding the role of Gal-1 in immune escape by tumors to make any strong conclusions/pathway reconstruction around this specific TME mechanism of action (MOA). To further strengthen the potential role of Gal-1 in tumor immune evasion we completed a series of preclinical in vivo and in vitro activities, using a highly selective Gal-1 small molecule inhibitor developed at Galecto Biotech. To examine the role of Gal-1 inhibition in vivo, we investigated the effects on tumor volume of the highly selective Gal-1 inhibitor, in a syngeneic mouse model of lung adenocarcinoma. RNA profiling of vehicle and compound treated tumors was also implemented following completion of the in-life phase. Oral administration of the Gal-1 inhibitor reduced mouse lung adenocarcinoma growth and increased the immune gene expression within the tumors, showing a strong association to that of exacerbated NK cell activity. No additional cytotoxic T cell gene changes were uncovered in the Gal-1 inhibitor treated tumors. We further evaluated the overall T cell compartment, relevant to the clinical TME setting, by stimulating human peripheral blood mononuclear cells (hPBMC’s) incubated with and without the Gal-1 inhibitor to observe the potential blockade of any known immune checkpoint inhibitor (ICI) resistance mechanisms. Interestingly, we found a variety of immune suppressive proteins to be inhibited, including IL-17, when hPBMC’s were incubated with the Gal-1 inhibitor. In summary, the data presented suggests highly selective Gal-1 inhibition could provide an effective, monotherapy (or be used in combination with ICI's) to boost immune infiltration and/or activation in the TME of lung adenocarcinoma and potentially other aggressive cancers. Citation Format: Ian Holyer, Rob Slack, Kristoffer Petersen, Fredrik Zetterberg, Alison Mackinnon. Preclinical evaluation of the role of Galectin-1 in tumor immune evasion associated mechanisms using a highly selective Galectin-1 small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB104.