(282e) Radiation-Induced Changes in Normal Tissues Alter Tumor Cell Recruitment

Authors: 
Rafat, M., Vanderbilt University
Graves, E. E., Stanford University
Hacker, B. C., Vanderbilt University
Alves, S. M., Vanderbilt University
Breast cancer metastasis remains a significant clinical problem linked to reduced patient survival. The role of the tissue microenvironment in local recurrence, however, is not well understood. We hypothesize that normal tissue irradiation (RT) influences tumor and immune cell behavior. In this study, we characterize the effects of RT on local and systemic cytokine secretion to evaluate how tumor-stromal interactions modulate tumor cell recruitment to sites of damage. This work represents an important step toward elucidating how changes in cytokine expression after RT contribute to tumor cell metastasis.

The impact of RT on local and systemic effects was studied using an orthotopic breast cancer model. BALB/c mice were inoculated with luciferase-labeled 4T1 murine breast cancer cells in the mammary fat pad (MFP). T cell populations were depleted using antibodies to CD8 as this cell population was previously shown to negatively regulate tumor cell recruitment. The contralateral normal MFP was irradiated to a dose of 20 Gy, and tumor cell recruitment was monitored with BLI 10 days after RT. Immunohistochemistry (IHC) was performed to stain irradiated and control tissues for F4/80 to determine the extent of macrophage infiltration. MFPs and blood were processed for Luminex immunoassay analysis at 0, 1, 5, and 10 days post-RT to evaluate the local and systemic effects of normal tissue irradiation.

RT promoted tumor cell migration to normal tissues in vivo when CD8+ T cells were depleted in comparison to immunocompetent mice (p<0.001). This increase in tumor cell recruitment following RT was preceded by significant F4/80+ macrophage infiltration locally. Luminex analysis of MFPs in mice lacking CD8+ T cells after RT showed an enhancement of cytokines that regulate the inflammatory microenvironment and influence tumor cell proliferation and invasion, including TGF-β and IL-6. Systemically, secretion of the immunomodulatory IL-28 was increased.

Our study establishes that cytokine signaling influences metastatic spread and tumor cell homing to damaged tissues. The altered cytokine secretion landscape underscores the importance of evaluating local and systemic cytokine gradients to determine factors involved in tumor cell recruitment. These results suggest that the tumor stroma may facilitate tumor regrowth and tumor cell invasion following radiation damage.

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