# Triple‐Negative Breast Cancer Cells Resist Natural Killer Cell‐Mediated Killing Through Interleukin‐11 Trans‐Signaling

## TL;DR

Triple-negative breast cancer cells use interleukin-11 to resist attacks from natural killer cells, offering a new target for improving cancer therapies.

## Contribution

The study identifies IL-11 trans-signaling as a novel mechanism by which TNBC cells evade NK cell-mediated killing.

## Key findings

- Resistant TNBC cells secrete high levels of IL-11, which forms complexes with sIL-11R.
- IL-11 trans-signaling activates the JAK1/STAT1/3/p21 pathway in NK cells, causing cell cycle arrest.
- Disrupting IL-11 or sIL-11R restores NK cell activity and reduces tumor resistance.

## Abstract

Natural killer (NK) cell‐based therapies show great promise for treating triple‐negative breast cancer (TNBC). However, in the tumor microenvironment, some TNBC cells develop resistance to NK cell‐mediated killing and contribute to NK cell exhaustion. In this study, TNBC cell populations are isolated that can resist NK cell attacks and uncovered the underlying mechanisms. It is found that these resistant TNBC cells secrete high levels of interleukin‐11 (IL‐11). IL‐11 acts through a process known as trans‐signaling by forming complexes with the soluble IL‐11 receptor (sIL‐11R) and engaging the gp130 receptor on NK cells. This trans‐signaling activates the JAK1/STAT1/3 pathway, leading to the upregulation of p21 and subsequent cell cycle arrest in NK cells. As a result, the proliferation and IFNγ production of NK cells are inhibited, enabling TNBC cells to resist NK cell‐mediated killing. Disrupting IL‐11 or sIL‐11R in TNBC cells restores NK cell activity. Importantly, it is also found that IL‐11 expression is elevated in human TNBC tissues and negatively correlated with the number of NK cells in the tumor microenvironment. These findings identify IL‐11 trans‐signaling as a novel mechanism of immune evasion in TNBC and suggest that targeting this pathway may enhance the effectiveness of NK cell‐based therapies.

Triple‐negative breast cancer cells express high levels of interleukin‐11 (IL‐11) that can form complexes with soluble IL‐11 receptor (sIL‐11R). These complexes can bind to gp130 on the membrane of natural killer (NK) cells through trans‐signaling to activate JAK1/STAT1/3/p21 downstream pathway. This activation arrests cell cycle progression of NK cells, decreasing their ability to attack breast cancer cells.