86P HEIH: A Novel Immunomodulatory LncRNA Tweaking NK Cells and TME in Triple-Negative Breast Cancer (TNBC) Patients

Immune-related long non-coding RNAs (lncRNAs) have been acknowledged as potential modulators in immune surveillance process. Given the scarcity of effective targeted therapies along with high immunogenicity of TNBC, immunotherapy was presented. In such context, immune checkpoint inhibitors (ICIs) were put through clinical trials however, prominent side effects and resistance prevaled. Thus, a promising approach would be targeting the innate arm of the immunity and sacking the immune suppressive tumor microenvironment (TME). LncRNAs were found to have a pivotal role in regulating Natural killer (NK) cells and tuning the TME. Hepatocellular carcinoma up-regulated EZH2-associated (HEIH) is a novel lncRNA that has been seldom examined in TNBC. So, our aim is to unravel the expression profile of the lncRNA HEIH in TNBC tissues, evaluate its oncological actions in TNBC cells and evaluate its unprecedented immunomodulatory role on NKG2D ligands and TME of TNBC. Breast biopsies were collected from 40 BC patients. MDA-MB-231 cells were cultured and transfected with different oligonucleotides. Total RNA was extracted and quantified by qRT-PCR. Cellular viability, colony forming ability and migration were measured using MTT, colony forming and scratch assays, respectively. HEIH was predominantly up-regulated in TNBC tissues compared to normal tissues as well as other BC subtypes. Functionally, knock down of HEIH resulted in a drastic reduction in cellular viability, colony forming ability and migration capacity of MDA-MB-231 cells. These set of results highlight HEIH as an oncogenic lncRNA in TNBC. Concerning its immunomodulatory role, HEIH siRNAs resulted in upregulation of the shedded NKG2D ligands MICA and MICB in TNBC cells. Moreover, Knockdown of HEIH caused considerable repression of the immune inhibitory cytokines, TNF-α and IL-10. The present study categorized HEIH as an oncogenic lncRNA that is solitarily expressed in TNBC patients and cell lines. Moreover, it constitutes the first major advancement in unraveling the immunomodulatory role of HEIH in boosting NK cells cytotoxicity and trimming TME in favor of TNBC eradication, thus proposing HEIH as a novel therapeutic target in TNBC.