Tumour-released Liver X Receptor ligands attract tumour promoting neutrophils in a CXCR2 dependent manner

Tumour formation is the result of molecular alterations involving cellular regulators as well as the ability of tumor cells to affect the tumor microenvironment through smoldering inflammation, or even taking advantage of inflammation to grow and metastasize. Tumour microenvironment is composed of various cell types, among them neutrophils are recognized as playing an important pro-tumorigenic role, by promoting neoangiogenesis and/or by suppressing antitumor immune responses. We have recently shown that ligands of liver X receptors (LXRs), which are involved in cholesterol homeostasis and in modulating immune responses, are released by cancer cells and suppress antitumor immune responses by dampening dendritic cell migration to draining lymph nodes. Here, we report that natural and tumour-derived LXR ligands attract a subpopulation of bone marrow (BM)- derived cells in a LXR independent, CXCR2 dependent manner. These cells have phenotypic (CD11bhighGr1highLy6G+) and morphological features of neutrophils and favour initial tumour angiogenesis. Moreover, the in vivo inactivation of LXR ligands, the depletion of neutrophils, as well as the pharmacologic and genetic inactivation of CXCR2 inhibit neutrophil recruitment to the tumour and delay tumour growth. Our data reveal an unanticipated chemoattractant role for tumour-derived LXR ligands in promoting tumour growth that relies on the CXCR2-mediated recruitment of neutrophils, thus identifying a new therapeutic target for cancer patients.