# NKGD2 Ligands (NKG2DLs) in Breast Cancer: In Silico Analysis and Narrative Review

## TL;DR

This paper explores the role of NKG2D ligands in breast cancer using in silico analysis and a literature review, highlighting their potential as immunotherapy targets.

## Contribution

The study provides a comprehensive in silico and narrative analysis of NKG2D ligands in breast cancer, revealing their expression patterns and therapeutic relevance.

## Key findings

- NKG2DL transcripts are consistently expressed in breast cancer cell lines and tumor tissues.
- Higher NKG2DL expression is associated with ductal histology, advanced tumor stage, and basal molecular subtype.
- NKG2DLs are detectable in tumor tissues but not in surrounding healthy tissues according to immunohistochemistry.

## Abstract

Breast cancer (BC) is a global health problem. BC is a biologically heterogeneous disease in which novel immunotherapeutic strategies are needed, particularly in the metastatic setting. The NKG2D/NKG2D ligand (NKG2DL) axis is a key component of innate antitumor immunity and represents a potential therapeutic target, but its relevance in BC has not been fully characterized. We performed an in silico analysis of NKG2DL expression in BC cell lines, healthy breast tissue, and tumor samples using publicly available transcriptomic databases (DSMZCellDive, ShinyTHOR, GTEx, TCGA, Human Protein Atlas), complemented by survival analyses from TCGA and KMPlot and a narrative review of the literature. NKG2DL transcripts were consistently expressed in BC cell lines and tumor tissues, with higher expression observed in ductal histology, higher tumor stage, and basal molecular subtype. Survival analyses showed heterogeneous and generally weak associations between individual NKG2DLs and clinical outcomes. In silico proteomics data are scarce, but the narrative review showed that NKG2DLs are expressed by immunohistochemistry in tumor tissues but absent in surrounding healthy tissues. The literature review also revealed concomitant dysfunction of NKG2D+ effector cells due to multiple resistance mechanisms (including ligand shedding). We also review potential therapeutic approaches.