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Sphingosine kinase 2 deficient tumor xenografts show impaired growth and fail to polarize macrophages towards an anti‐inflammatory phenotype

A challenging task of the immune system is to fight cancer cells. However, a variety of human cancers educate immune cells to become tumor supportive. This is exemplified for tumor‐associated macrophages (TAMs), which are polarized towards an anti‐inflammatory and cancer promoting phenotype. Mechanistic explanations, how cancer cells influence the macrophage phenotype are urgently needed to address potential anti‐cancer strategies along this line. One potential immune modulating compound, sphingosine‐1‐phosphate (S1P), was recently highlighted in both tumor growth and immune modulation. Using a xenograft model in nude mice, we demonstrate a supportive role of sphingosine kinase 2 (SphK2), one of the S1P‐producing enzymes for tumor progression. The growth of SphK2‐deficient MCF‐7 breast tumor xenografts was markedly delayed when compared with controls. Infiltration of macrophages in SphK2‐deficient and control tumors was comparable. However, TAMs from SphK2‐deficient tumors displayed a pronounced anti‐tumor phenotype, showing an increased expression of pro‐inflammatory markers/mediators such as NO, TNF‐α, IL‐12 and MHCII and a low expression of anti‐inflammatory IL‐10 and CD206. These data suggest a role for S1P, generated by SphK2, in early tumor development by affecting macrophage polarization. © 2009 UICC