Cancer Cells that Survive Radiation Lobectomy Display Markers of Increased Tumor Aggressiveness

Introduction: Radiation lobectomy (RL) is defined as the transarterial administration of high-dose radioactive microspheres to liver malignancies with the intent of inducing ipsilateral tumor ablation and contralateral liver hypertrophy. The biological characteristics of therapy surviving tumor cells and their microenvironment remain unstudied. Methods: Fourteen patients received RL, of which the colorectal liver metastasis group (n = 5 90Y, n = 2 166H-microspheres) is analyzed here. All metastases (n = 27) were selected from surgical pathology files. H&E and IHC stains with markers Ki67, CAIX, Olfm4 and CD45 were performed. A machine learning scoring protocol was established to classify tumor and non-tumor cells and allow unbiased quantification of staining intensities (Fig. 1A). Mandard regression grades were scored (Fig. 1B) and matched tumor-absorbed dose was determined on post-treatment PET/CT. Results: Metastases that received at least 60 Gy (90Y) regressed robustly, while lower dose portended variable response (Fig. 1C). Dose was positively correlated with hypoxia and proliferation, and negatively correlated with tumor stem cell-ness and cellular immune infiltrates. Perinecrotic tumor cells were highly hypoxic and stem cell-like, but not highly proliferative (Fig. 1D). Non-responsive lesions (regression grade 5) contained large numbers of cancer stem cells and cellular immune infiltrates. Conclusion: Tumor-absorbed dose is an important determinant of therapy response, but radiation-induced hypoxia and stem cell-ness may lead to aggressive tumor behavior. These data may augment our understanding of (non) radio-responsiveness and aid further evolution of RL in combination strategies aimed at curing hepatic malignancies.