A subpopulation of tumour-associated macrophages known to elicit a pro-tumoural response were previously identified to express the TIE2 receptor and hence known as TIE2-expressing monocytes/macrophages (TEMs). TEMs have been known to contribute to angiogenic responses and produce immunosuppressive factors in vivo, which contributes to tumour progression. We previously demonstrated that, ANG2 blockade in vivo inhibits tumour growth, tumour angiogenesis, TEMs perivascular localisation and tumour associated TIE2 upregulation in TEMs (1). Therefore, the TIE2-ligand ANG2 may control the expression of its receptor. Recent data, have also show that, ANG2 can promote an immunosuppressive phenotype in TEMs via IL10 upregulation (2). To further investigate the possible links between the proangiogenic and immunosuppressive activity of TEMs we asked whether ANG2 and or IL10 are modulating TIE2 expression in TEMs.
In addition, previous studies showed that selective depletion of TEMs inhibited the growth of primary tumours. It is, however, not clear whether TEMS are also involved in the pathogenesis of metastasis. Hence, the significance of TEMs in metastatic sites was explored.
Interestingly, treatment of the U937 monocytic cell line with ANG2 and/or IL-10 moderately increased TIE2 expression and IL-4 pre-polarisation of U937 cells further upregulated TIE2 expression. Using the 4T1.2 metastatic cell line in both experimental and spontaneous models of lung metastasis, we were able to show a reduction in the percentage of TIE2+ circulating monocytes, and an increase in the percentage of lung infiltrating TIE2+ macrophages in metastasis bearing mice. Confocal analysis confirmed the presence and perivascular localisation of MRC1+LYVE1+ TEMs in the metastatic lung. According to these data, the 4T1.2 model represent a valid model of metastatic breast cancer to further investigate the in vivo role of TEMs and the TIE2/ANG2/IL10 axis in tumour progression.