Primary Triple-negative Breast Tumours Induce Functional Impairment of Peripheral NK Cells — ASN Events
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  3. Primary Triple-negative Breast Tumours Induce Functional Impairment of Peripheral NK Cells

Primary Triple-negative Breast Tumours Induce Functional Impairment of Peripheral NK Cells (#138)

Theresa Harm 1 , Thomas Eder 2 , Florian Grebien 2 , Dagmar Gotthardt 2 , Sonia Vallet 1 3 , Dagmar Stoiber 1 4 , Agnieszka Witalisz-Siepracka 1 4
  1. Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems an der Donau, Austria
  2. Department of Biomedical Sciences and Pathobiology, University of Veterinary Medicine Vienna, Vienna, Austria
  3. Department of Internal Medicine 2, University Hospital Krems, Krems an der Donau, Austria
  4. These authors contributed equally, .

Breast cancer is the most common cancer diagnosed in women worldwide. 15-20% of breast tumours are classified as triple-negative, which is a very aggressive subtype. Metastasis to distant organs is more likely than in other subtypes and it is the main cause of patient death, which underlines the need for novel therapeutic approaches.

Natural killer (NK) cells are able to limit distant metastasis by eliminating tumour cells in the blood stream. However, NK-cell function is often suppressed by the cancer microenvironment, e.g. through the activation of immune checkpoints. Thus, the aim of this project is to analyse changes occurring in blood NK cells during the progression of metastatic triple-negative breast cancer (TNBC) to find novel therapeutic targets.

Blood NK cells from primary TNBC tumour-bearing mice and healthy controls were subjected to 10x Genomics single-cell RNA sequencing. The identified targets and NK-cell functionality were validated ex vivo and in vitro using a co-cultivation system of NK and breast cancer cells. In addition, flow cytometric analysis of various organs was performed at the primary tumour stage of the TNBC mouse model.

Single-cell RNA sequencing showed a strong enrichment of blood NK cells with an activated signature in primary-tumour bearing mice. However, degranulation-related genes were downregulated in this cluster. Ex vivo functional analysis confirmed the reduced degranulation potential of peripheral NK cells from tumour-bearing mice. Similar changes in the NK cell phenotype could be mimicked by an in vitro co-cultivation system of NK and TNBC cells. Currently, targeting of relevant genes that might reverse the observed phenotype is explored.

Systemic alterations in NK cells are already present at the primary tumour stage, which potentially dampens their potential to limit TNBC metastasis. Further analysis of targets contributing to this functional impairment could provide new therapeutic targets to limit metastasis in patients.