Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue
- 1Vanderbilt University
Abstract
Recurrence remains a significant clinical challenge for triple-negative breast cancer patients and radiotherapy (RT) is a key therapeutic tool that significantly reduces the risk of relapse. Despite this, patients with chronic lymphopenia and a high neutrophil:lymphocyte ratio (NLR) experience recurrence at significantly higher rates than those whose hematological biomarkers return to baseline post-RT, and there are currently no treatments to prevent this relapse. Here, we utilized in vivo mouse models of lymphocyte-deficiency to identify the mechanism behind systemic immune status and recurrence. Using a model of RT-induced circulating tumor cell (CTC) colonization, we found that neutrophils are sustained in the irradiated, lymphocyte-deficient mammary tissue up to 10 days post-RT. Persistent neutrophil accumulation was accompanied by excessive vascular remodeling and tumor cell colonization of the mammary tissue, both of which were abated upon systemic neutrophil depletion. Neutrophils in the colonization-permissive microenvironment exhibited a state of pathological activation consistent with a polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype that was not seen in systemic compartments, highlighting a microenvironment-induced phenotype shift. This phenotype was recapitulated in vitro when naive neutrophils were exposed to the secretome of RT-induced senescent endothelial cells (ECs). We found that these activated neutrophils then regulated the dysfunction of irradiated ECs in a canonical NF-kB-dependent manner, increasing their barrier permeability and activating downstream inflammatory signals. Our findings not only establish neutrophils as a critical component of tumor cell colonization in lymphocyte-deficient subjects but also uncover a positive feedback loop between neutrophils and irradiated vasculature that leads to aberrant tissue remodeling and ultimately tumor cell colonization. This work deepens our understanding of how systemic factors influence treatment-damaged microenvironments, which could ultimately lead to identification of molecular targets for prevention of RT failure.
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BibTeX
@misc{martello2026radiotherapyinduced,
title = {{Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue}},
author = {S. E. Martello and B. H. Stevenson and H. Korbey and K. C. Corn and T. Zhu and E. J. Lin and M. Paul and K. E. Stubenrauch and J. Wang and A. Perez and M. Rafat},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.03.756445},
url = {https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Radiotherapy-induced vascular dysfunction alters neutrophil phenotype to promote tumor cell colonization of mammary adipose tissue
AU - S. E. Martello
AU - B. H. Stevenson
AU - H. Korbey
AU - K. C. Corn
AU - T. Zhu
AU - E. J. Lin
AU - M. Paul
AU - K. E. Stubenrauch
AU - J. Wang
AU - A. Perez
AU - M. Rafat
PY - 2026
DA - 2026/10/03
PB - bioRxiv
DO - 10.64898/2026.10.03.756445
UR - https://www.biorxiv.org/content/10.64898/2026.10.03.756445v1
AB - Recurrence remains a significant clinical challenge for triple-negative breast cancer patients and radiotherapy (RT) is a key therapeutic tool that significantly reduces the risk of relapse. Despite this, patients with chronic lymphopenia and a high neutrophil:lymphocyte ratio (NLR) experience recurrence at significantly higher rates than those whose hematological biomarkers return to baseline post-RT, and there are currently no treatments to prevent this relapse. Here, we utilized in vivo mouse models of lymphocyte-deficiency to identify the mechanism behind systemic immune status and recurrence. Using a model of RT-induced circulating tumor cell (CTC) colonization, we found that neutrophils are sustained in the irradiated, lymphocyte-deficient mammary tissue up to 10 days post-RT. Persistent neutrophil accumulation was accompanied by excessive vascular remodeling and tumor cell colonization of the mammary tissue, both of which were abated upon systemic neutrophil depletion. Neutrophils in the colonization-permissive microenvironment exhibited a state of pathological activation consistent with a polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype that was not seen in systemic compartments, highlighting a microenvironment-induced phenotype shift. This phenotype was recapitulated in vitro when naive neutrophils were exposed to the secretome of RT-induced senescent endothelial cells (ECs). We found that these activated neutrophils then regulated the dysfunction of irradiated ECs in a canonical NF-kB-dependent manner, increasing their barrier permeability and activating downstream inflammatory signals. Our findings not only establish neutrophils as a critical component of tumor cell colonization in lymphocyte-deficient subjects but also uncover a positive feedback loop between neutrophils and irradiated vasculature that leads to aberrant tissue remodeling and ultimately tumor cell colonization. This work deepens our understanding of how systemic factors influence treatment-damaged microenvironments, which could ultimately lead to identification of molecular targets for prevention of RT failure.
ER -