# Transient adenovirus-Cre infection causes long-lasting remodeling of the mammary gland immune landscape

## TL;DR

This study shows that using adenovirus to trigger genetic changes in mammary glands causes lasting immune changes that can affect cancer research interpretations.

## Contribution

The study reveals that adenovirus-induced Cre expression alters immune dynamics more persistently than tamoxifen-based methods in mammary tumor models.

## Key findings

- Adenovirus causes long-term immune changes, including persistent CD8+ T-cell infiltration dominated by CD103+ tissue-resident T cells.
- Adenovirus skews CD4+ T cells toward antiviral states and reduces myeloid cells, unlike tamoxifen-induced p53-loss.
- Adenovirus-induced immune effects can obscure p53-loss-driven immune activation, complicating early tumor-immune interaction studies.

## Abstract

Understanding how immune cells respond to early oncogenic events is essential for designing immune-based strategies to intercept breast cancer. Mouse models that induce mammary tumorigenesis through Cre-mediated genetic manipulations can be used to study these early events. However, the immune effects of different induction methods remain unclear. Here, we compare adenovirus-delivered Cre with tamoxifen-inducible CreER systems in models targeting luminal mammary epithelial cells for p53-loss. We find that transient intraductal adenoviral infection produces not only an acute immune response but also long-lasting reshaping of the mammary gland immune microenvironment. Adenovirus exposure induces robust and persistent CD8+ T-cell infiltration dominated by CD103+ tissue-resident T cells displaying heightened activation. This sustained antiviral T-cell signature obscures the p53-loss-driven CD8+ T-cell activation detectable in the CreER/tamoxifen model. Adenoviral infection also transiently skews CD4+ T cells toward IFN-γ-producing antiviral states and compresses the myeloid compartment, whereas tamoxifen-induced p53-loss increases macrophage abundance and activates CD8+ T-cells during premalignancy. Despite similar tumor latencies across induction strategies, our findings demonstrate that adenoviral infection exerts long-term immunological effects that can confound interpretation of immune dynamics during early mammary tumorigenesis. These results emphasize the importance of induction-method selection when using genetically engineered mouse models to study cancer-immune interactions.