CXCL11-CXCR3 axis mediates tumor lymphatic crosstalk and inflammation induced tumor promoting pathways in head and neck cancers.

Tumor metastasis to the draining lymph nodes is an important indicator of patient prognosis and is tightly regulated by molecular interactions mediated by lymphatic endothelial cells (LECs). However, these mechanisms remain undefined in the head and neck squamous cell carcinomas (HNSCC). HNSCC cells and LECs were used to determine the specific pathways mediating tumor-lymphatic crosstalk. We investigated the effects of a pentacyclic triterpenoid, methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF DODA-Me) that is a potent anticancer agent on cancer-lymphatic interactions. In response to inflammation, LECs induced the CXCL9/10/11 chemokines with a concomitant increase in the CXCR3 receptor in tumor cells. CF DODA-Me showed anti-proliferative effects on tumor cells, altered cellular bioenergetics and suppressed matrix metalloproteinases (MMPs) and chemokine receptors. It also suppressed the induction of CXCL11-CXCR3 axis and PI3K/AKT pathways. Tumor cell migration to LECs was inhibited by blocking CXCL11 while recombinant CXCL11 significantly induced tumor migration, epithelial to mesenchymal transition and matrix remodeling. Immunohistochemical analysis of HNSCC tumor arrays showed enhanced expression of CXCR3 and increased lymphatic vessel infiltration. Further, TCGA RNA-Seq data from HNSCC patients also showed a positive correlation between CXCR3 expression and lympho-vascular invasion. Collectively, our data suggest a novel mechanism for crosstalk between the LECs and HNSCC tumors through the CXCR3-CXCL11 axis and elucidates the role the triterpenoid CF DODA-Me in abrogating several of these tumor promoting pathways.