# Role of IFN-lambda in Promoting Breast Cancer Metastasis

> **NIH NIH R01** · RUSH UNIVERSITY MEDICAL CENTER · 2020 · $356,688

## Abstract

Distant metastases are the cause of approximately 90% of deaths due to breast cancer (BC). During BC
development, novel properties are acquired by metastatic BC cells, allowing them to spread and escape
immune system control. Recent studies on patients with early BC strongly suggest the involvement of NK cells
in the control of tumor development. However, during metastasis, tumor cells may compromise the
mechanisms of NK cell targeting and escape NK cell control. Therefore, towards identifying immune-related
factors associated with BC aggressiveness, we analyzed microarray databases of human BC specimens and
established BC cell lines. We specifically focused on interferon (IFN)-related transcripts due to the important
impact of type I IFNs on anti-cancer responses. Importantly, we observed that the expression of IFN-lambda
(IFN-λ) receptor 1 (IFNLR1), the unique receptor for the newly discovered type III INF-λ, negatively correlates
with ER expression. Furthermore, we discovered a significant difference in the IFN-λ response between
primary and metastatic tumor cells. Specifically, in contrast to primary tumor cells, which lack IFNLR1
expression, metastatic cells express IFNLR1 and are responsive to IFN-λ, as measured by STAT1 activation.
Ex vivo culture of metastatic BC cells with IFN-λ leads to accelerated in vivo metastasis. In addition, in mouse
metastatic BC cells, we found that IFN-λ down-regulates H60, a ligand for NK cell activation receptor NKG2D,
and renders BC resistant to NK cell lysis. Our preliminary data indicate that the induction of IFNLR1 expression
on BC cells is associated with the promotion of distal metastasis, which is fatal for BC patients due to a current
lack of efficient therapy. Our data also indicate that an independent increase in endogenous IFN-λ may fuel BC
spread. We hypothesize that in addition to inhibiting NK cell tumor killing, IFN-λ signaling in BC cells may
induce tumor migration and invasion. IFN-λ-induces NKG2D ligand down regulation and may afford metastatic
BC cells with resistance to NK cell-mediated killing. To test the in vivo impact of IFNLR1 signaling on distal
metastasis, we propose to generate murine and human BC cell lines with differential IFNLR1 expression and
monitor their metastatic potential in immune competent mouse tumor models and immune-reconstituted human
xenograft tumor models. We also propose to examine the impact of genetic ablation of IFNLR1 on in vivo distal
tumor metastasis in syngeneic IFNLR1-/- MMTV-PyMT mice and in vivo silencing of IFNLR1 in our autologous
immune-reconstituted patient-derived xenograft (AIR-PDX) model. To determine the molecular mechanism(s)
underlying IFN-λ-mediated downregulation of NKG2D ligands, we plan to investigate the effect of IFN-λ on the
inhibition of NKG2D ligand gene expression via miRNA or shedding of NKG2D ligands through the activation of
matrix metalloproteinases. We believe that investigating the role of the IFN-λ/IFNLR axis is crucial for
de...

## Key facts

- **NIH application ID:** 9985763
- **Project number:** 5R01CA225993-03
- **Recipient organization:** RUSH UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Ahmed Lasfar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,688
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985763

## Citation

> US National Institutes of Health, RePORTER application 9985763, Role of IFN-lambda in Promoting Breast Cancer Metastasis (5R01CA225993-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9985763. Licensed CC0.

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