Immune-Stimulatory Effects of Curcumin on the Tumor Microenvironment in Head and Neck Squamous Cell Carcinoma

SIMPLE SUMMARY: Head and neck squamous cell carcinoma has been shown to downregulate the host’s antitumor immune response as well as inherent anticancer immunity, inter alia, via increased activation of nuclear factor kappa of activated B-cells (NF-κB). The aim of this study is to examine curcumin’s effects on certain pro- and antitumoral chemokines via NF-κB, as well as the combined effects of curcumin and toll-like receptor 3 agonist Poly I:C on NF-κB and regulatory T-cell attraction. Furthermore, we compare curcumin with established NF-κB inhibitors caffeic acid phenethyl ester and BAY 11-7082. We demonstrate that curcumin has immune-modulating effects, with potent inhibition of the regulatory T-cell-attracting effects of Poly I:C. Therefore, curcumin presents an adjuvant that not only improves the effects of established therapies but also holds the potential to reduce negative side effects in tumor entities with increased NF-κB activation. ABSTRACT: Curcumin is known to have immune-modulatory and antitumor effects by interacting with more than 30 different proteins. An important feature of curcumin is the inhibition of nuclear factor kappa of activated B-cells (NF-κB). Here, we evaluate the potential of curcumin to reverse the epithelial to mesenchymal transition (EMT) of head and neck squamous cell carcinoma (HNSCC) cells as a part of tumor escape mechanisms. We examined the impact of curcumin on the expression of different pro- and antitumoral chemokines in ex vivo HNSCC tumor tissue and primary macrophage cultures. Further, we evaluated the combinatorial effect of curcumin and toll-like receptor 3 (TLR3) agonist Poly I:C (PIC) on NF-κB inhibition and regulatory T-cell (Treg) attraction. Mesenchymal markers were significantly reduced in cancer specimens after incubation with curcumin, with simultaneous reduction of key transcription factors of EMT, Snail, and Twist. Furthermore, a decrease of the Treg-attracting chemokine CCL22 was observed. Additionally, curcumin-related inhibition of NF-κB nuclear translocation was evident. The combination of PIC with curcumin resulted in further NF-κB inhibition, whereas PIC alone contrarily resulted in NF-κB activation. Furthermore, curcumin was more effective in inhibiting PIC-dependent NF-κB activation and Treg attraction compared to known NF-κB inhibitors BAY 11-7082 or caffeic acid phenethyl ester (CAPE). The presented results show, for the first time, the immune-modulating effects of curcumin in HNSCC, with potent inhibition of the Treg-attracting effects of PIC. Hence, curcumin presents a promising drug in cancer therapy as a supplement to already established treatments.