Taken together these data support our hypothesis that engagement of CXCR4 or S1P5 with their cognate ligands creates a positive feedback loop driving one another’s upregulation, in line with our proposed model of S1P1/5 and CXCR4-mediated NK cell desensitization to stimulation by tumor cells (Fig. 6L). Here, S1PR5 is linked to neoplasm.