Abstract PS2-12-07: Metabolic and immune reprogramming via SCD1 inhibition enhances chemo-immunotherapy response in TNBC

Abstract Background: Triple-negative breast cancer (TNBC) is highly aggressive subtype with poor prognosis and there is an urgent need to develop novel therapies. Deregulated cellular energetics is a known hallmark of cancer. Stearoyl-CoA desaturase-1 (SCD1), is a key enzyme in fatty acid (FA) synthesis, converting saturated to monounsaturated FA. It is upregulated in TNBC, and its expression correlates with poor survival. Hence, targeting SCD1 is a novel strategy for cancer therapy. We have developed an SCD1 inhibitor, MTI-301 and shown anti-tumor activity in murine TNBC cell lines with MTI-301 alone and in combination with paclitaxel. Here, we study the efficacy of MTI-301 in TNBC mouse model and, molecular and immunological association of SCD1 in TNBC. Methods: MTI-301 activity (10 mg/kg oral gavage daily) was evaluated in E0771 immunocompetent TNBC mouse models alone and with immune checkpoint inhibitors (ICI) and paclitaxel (anti-PD-L1 Ab 200ug/mouse; IP and 25 mg/kg IP both given 2/week). Immune markers such as CD4+ T cell and CD8+ T cell in mice tumor tissue were assessed by immunohistochemistry (IHC). Tumor volume was measured by calipers 2/week and compared between groups by ANOVA test. Molecular and immune characterization was performed in 1,581 invasive ductal (ID) TNBC patient (pt) samples tested by NGS (592-gene panel, NextSeq; WES/WTS, NovaSeq; Caris Life Sciences, Phoenix, AZ). ID-TNBC SCD1-high(H) and SCD1-low(L) RNA expression were classified as above or below the 50 percentiles, respectively. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Pathway enrichment was determined by GSEA (Broad Inst). Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q