175P - MicroRNA-548c: An Immune-Activator microRNA at the Tumor Microenvironment and Immune Milieu of Breast Cancer

Background

Cancer cells evade the human immune system by manipulating the tumor-immune microenvironment (TIME) via suppressing the immuno-activator and promoting the immune-suppressive mediators. Hence, targeting immuno-modulatory factors became an ingenious treatment option, particularly for cancer types that shows scarcity of treatment options such as triple negative breast cancer (TNBC). Novel immuno-modulatory targets such as Galectin (GAL) 3 and 9 have been found to be overexpressed in TNBC, repressing the immune surveillance. Similarly, TNBC tumors were found to prevent the activation of immune infiltrating lymphocytes via overexpressing immune checkpoint CD155 expression on its surface. MHC class I polypeptide–related sequence A (MICA) and MICB are stress-induced ligands essential for innate immunity activation at the TIME. However, their expression is also often suppressed in TNBC, leading to immune suppression and poor prognosis. Our research group has extensively worked on microRNAs to modulate multiple targets simultaneously. Hence, this work unravels the expression profile of the miR-548c in BC tissues, evaluate its unprecedented immunomodulatory role in TNBC via altering GAL3/9, CD155, and MICA/B expression.

Methods

BC female patients (n=20) were recruited. In-silico analysis was used to identify miRNAs that target immunomodulatory targets. MDA-MB-231 TNBC cells were cultured and transfected by oligonucleotides. Total RNA was extracted using Biazol, reverse transcribed and quantified using qRT-PCR.

Results

miRNA-548c is a down-regulated tumor suppressor miRNA in BC tissues compared to its normal counterparts. MiRNA-548c was validated to regulate the immunogenic profile in TNBC. Given the overexpression of the immuno-suppressive GAL3, GAL9, and CD155, miR-548c simultaneously constrained their expression in TNBC cells. Moreover, ectopic expression of miR-548c in MDA-MB-231 cells resulted in a marked upregulation of the expression of the immuno-activators MICA and MICB, enhancing the overall immunogenic profile of TNBC cells.

Conclusions

This study identifies miRNA-548c as a booster of the immune surveillance by concomitant adjustment for the immunogenic ligands expressed/produced by the TNBC cell.

Legal entity responsible for the study

The authors.

Funding

This work was supported by Swiss National Science Foundation (SNSF), grant IZSTZ0_198887.

Disclosure

All authors have declared no conflicts of interest.