30P Expression signature of Let-7a, miR-34a and miR-486-5p in young triple-negative breast cancer patients overexpressing PDL1: A step towards precision immuno-oncology

In an era of immunotherapeutic approaches, immune checkpoint blockers (ICBs) have revolutionised the oncology market. Yet, most patients do not benefit. The new direction has shifted towards identifying novel predictive biomarkers in the field of precision immuno-oncology. Thus, the development of a multifactorial synergistic predictive-model has become a pressing need. Triple-negative breast cancer (TNBC) and especially at younger age (<40 years) tends to exhibit an aggressive phenotype evading immune surveillance mediated by immune cells. This occurs by overexpressing PDL1 and shedding of CD155. Our group has recently identified sONE, a tumor suppressor lncRNA that is absent in young TNBC patients. sONE functional activity was found to be directly correlated to other immunomodulatory microRNAs. However, their expression signature in young TNBC patients has never been investigated. The aim of this study was to identify an immunomodulatory-related miRNA signature for young TNBC patients. TNBC patients (n=28) were recruited. Median age at the time of diagnosis was 39 years old (range 22-70). Lymph node metastasis was evident in 60.7%. High Ki-67 ( >15) was observed in 71%. Stage 3 diagnosis was evident in 53.6 %of patients. Almost 93% of tumors were invasive ductal carcinoma (IDC) and the rest were invasive lobular carcinoma (ILC). Tumor size >5 cm was recorded in 68%. RNA was extracted from tissues and serum, reverse transcribed and quantified using q-RT-PCR. TNBC cell lines were cultured, transfected using oligonucleotides using lipofection. An elevated expression pattern for PDL1 in young TNBC patients and a marked repression of CD155, let-7a, miR-34a and miR-486-5p compared to the older group were observed. Ectopic expression of let-7a and miR-34a resulted in a significant repression of PDL1 while miR-486-5p mimics resulted in an induction of CD155 levels. Such an immuno-modulatory miRNAs expression pattern was inversely correlated with tumor size and Ki-67 in TNBC patients. Yet, PDL1 was directly associated with lymph node metastasis and stage of disease. This study identified a panel of three immunomodulatory miRNAs as a signature among young TNBC patients overexpresing PDL1 and underexpressing CD155.