Abstract 28P
Background
Deregulated lipogenesis is essential for tumor cell survival. Regardless of circulating lipid levels, a wide range of tumors presents accelerated de novo fatty acid synthesis. Oncogenic lipogenesis is manifested by enhanced activity and coordinated expression of multiple lipogenic enzymes including ATP-citrate lyase (ACLY) in tumor cells. Therefore, the present study was aimed at understanding the influence of ACLY on breast tumorigenesis and its role in inducing immune escape.
Methods
We analyzed The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets using an R statistical environment to understand the correlation between lipogenic enzymes and immune regulatory genes. Expression levels of ACLY and PDL-1/AKT/mTOR signaling proteins in different breast cancer cells were quantified using immunoblotting. The siRNA-mediated ACLY knockdown was conducted and the subsequent effect on cell cycle and cell death were quantified using flow cytometry. The expression levels of inflammatory markers are quantified using enzyme-linked immunosorbent assay (ELISA). The expression of immune-regulatory genes in ACLY knockdown cells were quantified using real-time PCR.
Results
Our TCGA and CPTAC analysis revealed that lipogenic enzymes- ACLY, FASN, ACACA were deregulated in breast cancer and were correlated with immune regulatory genes including PD-L1. The siRNA-mediated knockdown demonstrated that ACLY modulated PDL-1 via AKT/mTOR signaling. ACLY knockdown also resulted in significant cell cycle arrest and cell death which was also reflected in the expression of Bcl-2, survivin, and caspase. The expression of TNFa and IL-8 were found to be elevated while IL-4 was found to be unaltered in the conditioned medium of ACLY knckdown cells. Furthermore, the ACLY knockdown in breast cancer cells led to aberrant expression of immune regulatory genes including CD27, CD40, CD47 and TNFSF4 indicating deregulated expression of ACLY in breast tumor cells mediates immune escape.
Conclusions
This is the first study that shows ACLY influences PD-L1 leading to aberrant expression of immune regulatory genes and tumor cell survival in breast cancer.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.