The central role of tumor-evoked Bregs in breast cancer metastasis as inducers of metastasis-promoting Tregs and myeloid-derived suppressive cells. (TUM4P.903)

Abstract

Abstract We recently found that, by utilizing metabolites of 5-lipooxygenase, highly metastatic 4T1 breast cancer induces the generation of unique subset of regulatory B cells, tBregs1,2. The role of tBregs in metastasis is that they induce conversion of FoxP3+ regulatory T cells (Tregs) that protect metastasizing cells by inactivating antitumor effector NK cells and CD8+ T cells 1,3. The absence of tBregs or a B-cell deficiency in μMT mice is sufficient to disable the ability of 4T1 cancer cells to metastasize into the lungs. Although in this model the myeloid-derived suppressive cells (MDSC) have been shown to also promote metastasis, surprisingly we failed to associate their importance in metastasis. MDSC are normally expanded (an assumed pro-metastatic requirement) without apparent phenotypic changes in B-cell deficient mice or if tBregs are inactivated. However, adoptive transfer of MDSC from tumor-bearing WT mice, but not μMT mice, is able to restore lung metastasis of 4T1 cancer in μMT mice, suggesting that tBregs may be needed for the education of MDSC. Here we provide the mechanistic proof that tBregs indeed render MDSC pro-metastatic. tBregs target and use relatively small subset of MDSC. Thus, our data not only uncover previously unknown regulatory pathway, but also suggest a cautious new interpretation on the importance of MDSC in metastasis. 1 Olkhanud, P. B. et al. Cancer Res. 2011. 2 Wejksza, K. et al. J.Immunol. 2013. 3 Olkhanud, P. B. et al. Cancer Res. 2009.