Brain Metastasis: the Impact of Surgical Stress, Immune Stimulation and NK Cells

Brain metastasis (BrM) have poor prognosis, and prophylactic approaches are scarce. Surgical stress

responses have been shown to promote metastasis in peripheral organs through their immune-suppressive

impacts and through direct effects on the malignant tissue and host physiology. However, BrM have not

been studied in these respects, and the unique brain immune milieu, blood supply, and BBB, may react

differently to such neuroendocrine challenges. Thus, we studied the effect of laparotomy, role of NK cells,

and CpG-C immune-stimulation – a TLR-9 agonist having minimal adverse effects in humans – in early

stages of brain and lung metastasis. Two syngeneic animal models were used: 3LL/D122 in C57BL/J6

mice, and MADB106 mammary adenocarcinoma in F344 rats. Tumor cells were injected either through the

tail vein or employing a novel internal carotid injection approach we have developed, which generates BrM

with high efficacy and minimal injection-related interferences to cerebral blood flow. Employing both

models and inoculation approaches in naïve and NK-depleted animals, our results indicate that NK cells

surprisingly have no impact on BrM, while profoundly controlling lung metastases. On the other hand,

laparotomy significantly enhanced brain and lungs tumor infiltration, and CpG-C reduced it, overcoming the

effects of laparotomy. Thus, surgery is a significant risk factor for BrM through yet unknown mechanisms,

and CpG-C treatment may be used prophylactically in cancer patients.