The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer.

BACKGROUND: Despite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug. METHODS: We carried out the western blot and small interfering RNA (siRNA) transfection assay to evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immunofluorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4-nitroquinoline-1-oxide (4-NQO) oral cancer model. RESULTS: We found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8+ cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased T-cell proliferation, tumor-infiltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8+ T cells. In addition, Curcumin inhibited expression of CD4+CD25+FoxP3+ Treg cells as well as PD-1 and TIM-3. CONCLUSIONS: These results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.

Effectiveness of percutaneous neuromuscular electrical stimulation for neck pain relief in patients with cervical spondylosis.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of percutaneous neuromuscular electrical stimulation (PNMES) for treating neck pain in patients with cervical spondylosis (CS). METHODS: One hundred and twenty four patients with neck pain of CS were included, and then they were randomly divided into a PNMES group and a control group in a ratio of 1:1. All patients received PNMES or sham PNMES 30 minutes daily, 3 times weekly for 12 weeks. The primary outcome was assessed by the visual analog scale (VAS). The secondary outcomes were evaluated by the cervical range of motion (ROM), neck disability index (NDI) score, as well as the adverse events (AEs). All outcome measurements were measured at the end of 12-week treatment, and 4-week follow-up after treatment. RESULTS: At the end of the 12-week treatment, and 4-week follow-up, the patients receiving PNMES exhibited more decrease in the mean VAS (P < .01), and NDI (P < .01) respectively, compared with the patients receiving sham PNMES. Additionally, the increase in the mean ROM was also significantly higher in the PNMES group than that in the sham PNMES group at the end of the 12-week treatment, and 4-week follow-up, respectively (P < .01). No AEs were found in either group. CONCLUSIONS: The results of this study demonstrated that PNMES is more effective than Sham PNMES for neck pain relief in patients with CS.