The antitumor effect of tlr4 inhibition in head and neck cancer cell lines

Head and neck cancers (HNC) are a group of heterogeneous tumors frequently associated with high-risk HPV or TP53 mutations. HPV-positive cancers are associated with a better prognosis, whereas TP53-mutated tumors are frequently more aggressive. Effective treatment for advanced-stage and metastatic disease is still unavailable. The role of innate immunity in cancer has not been fully explored, and Toll-like receptor 4 (TLR4) has been demonstrated to be an interesting molecular therapeutic target for several types of cancer. Here, we used four HNC cell lines with different molecular profiles, including mutations in TP53 and HPV infection, and evaluated the effect of the TLR4 pathway on tumorigenesis by modulating its activity via the agonist lipopolysaccharide (LPS) and the inhibitor TAK242. We showed that the induction of the TLR4 pathway increased proliferation in the SCC78 and SCC143 cell lines, whereas the inhibition of TLR4 decreased proliferation, colony formation capacity, and migration in all the cell lines studied. TLR4 inhibition reduced IL-6 mRNA expression in SCC78 and SCC143, and MKI67 in SCC78. Also, TAK242 downregulated p53 pathway in SCC78, a TP53 GOF mutation cell line. In combination with cisplatin, TAK242 demonstrated an additive effect, increased cisplatin sensitivity in SCC154, and altered the death mechanism induced by cisplatin in SCC78 cells. In conclusion, TLR4 inhibition led to antitumor effects independent of HPV infection status or TP53 status, suggesting that TLR4 may be a broad-spectrum target for HNC therapy.