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

Abstract

BackgroundDespite 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. MethodsWe 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. Immuno uorescence, 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 4nitroquinoline-1-oxide (4-NQO) oral cancer model. ResultsWe 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 Tcell proliferation, tumor-in ltrating 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. ConclusionsThese results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multilevel (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.

Effects and Mechanisms of Curcumin for the Prevention and Management of Cancers: An Updated Review

“…Moreover, curcumin suppressed ovarian cancer growth in xenograft models by up-regulating circ-PLEKHM3 [ 86 ]. Curcumin could also reduce a transformative phenotype and tumor formation in the 4-nitroquinoline-1-oxide-induced head and neck cancer model, and tumor volume was significantly reduced after curcumin treatment [ 63 ]. Another study found that curcumin significantly reduced tumor weight and tumor size in BALB/c nude mice with SGC-7901 gastric cancer cells’ subcutaneous xenografts by promoting miR-34a expression [ 68 ].…”

Cold atmospheric plasma: Novel opportunities for tumor microenvironment targeting

“… 19 Increased CD8 + cytotoxic T cells and suppressed Treg activity as triggered by curcumin was reported to be associated with halted head and neck cancer cell invasion. 20 On the contrary, decreased CD8 + T cell density coupled with elevated Treg TME infiltration resulted in impaired IFNγ release from TILs and consequently a suppressive T cell contexture and accelerated colorectal cancer progression. 21 Accordingly, low CD8 + T cell and high Treg density was suggested as an useful index prognostic of poor lung adenocarcinoma outcome, alone or coupled with other biomarkers.…”

Therapeutic Implications of UVB Irradiation in Cancer by Enhancing Anti‐Tumor Immunity†

“…Thus, targeting immunosuppressive CD4 + T regulatory cells and rescuing CD8 + cytotoxic effector T cells is known to be a successful approach to enhance anti-tumor immunity and regression of tumor growth and metastasis. Various immunomodulatory drugs and molecules have been developed to enhance anti-tumor immune response but all of them have limitations due to their off-targeting effects or toxicity (15)(16)(17). Accumulating evidence suggests that chronic exposure of UV radiation induces an immunosuppressive tumor microenvironment in skin tumor via diminishing antigen-presenting cell function, increasing production of immunosuppressive cytokines, and modulating contact and delayed type of hypersensitivity during skin carcinogenesis (18).…”