# The CXCL10/CXCR3 axis is essential for sustaining immunological dormancy in triple-negative breast cancer

## TL;DR

The CXCL10/CXCR3 pathway helps keep triple-negative breast cancer in a dormant state by supporting immune control, and targeting this pathway could improve patient outcomes.

## Contribution

Identifies CXCL10/CXCR3 as a novel axis regulating dormancy in triple-negative breast cancer through immune modulation.

## Key findings

- CXCL10/CXCR3 sustains dormancy by maintaining an anti-tumor immune environment in triple-negative breast cancer.
- Blocking CXCL10/CXCR3 leads to tumor growth in immune-competent mice but not in immune-deficient mice.
- A CXCL10-based dormancy signature correlates with improved survival in TNBC patients.

## Abstract

Immune surveillance plays a pivotal role in controlling tumor emergence, dormancy and progression, including in breast cancer. Despite its potential clinical relevance, the mechanisms governing dormancy initiation, maintenance and escape, as well as the molecular mediators involved, remain poorly understood. Here, we identify the interferon-inducible chemokine CXCL10 and its receptor CXCR3 as key regulators of immunological dormancy in triple-negative breast cancer (TNBC). By transcriptomic profiling, we observed high expression of Cxcl10 in dormant cells in two different orthotopic, syngeneic models of breast cancer dormancy (D2.0R and 4T1-MR20). Genetic silencing of Cxcl10 in dormant cells or pharmacological blockade of CXCR3 in vivo led to early tumor onset and rapid growth in immunocompetent mice. In contrast, dormant cells effectively formed tumors in immune-deficient mice independently of Cxcl10 status, demonstrating that the CXCL10/CXCR3 axis-mediated dormancy requires a functional immune system. Further analysis confirmed that Cxcl10 silencing altered the local immune microenvironment, reducing CD4+ and CD8+ T cell infiltration while increasing the presence of granulocytic Myeloid Derived Suppressor Cells and Natural Killer cells. Moreover, Cxcl10 silencing significantly increased the burden of tumor cells disseminated to the lung. Leveraging these findings, we identified a CXCL10-mediated dormancy signature that predicts improved overall survival in TNBC patients. Our findings have identified a new mechanism modulating breast cancer dormancy with two important clinical implications: the CXCL10/CXCR3 axis as a potential therapeutic target for improving survival of patients with TNBC, and the CXCL10-dependent dormancy signature as a tool for identifying these patients.