The roles of curcumin in regulating the tumor immunosuppressive microenvironment

Abstract

Cancer is a harmful threat to human health. In addition to surgery, a variety of anticancer drugs are increasingly used in cancer therapy; however, despite the developments in multimodality treatment, the morbidity and mortality of patients with cancer patients are on the increase. The tumor-specific immunosuppressive microenvironment serves an important function in tumor tolerance and escape from immune surveillance leading to tumor progression. Therefore, identifying new drugs or foods that can enhance the tumor immune response is critical to develop improved cancer prevention methods and treatment. Curcumin, a polyphenolic compound extracted from ginger, has been shown to effectively inhibit tumor growth, proliferation, invasion, metastasis and angiogenesis in a variety of tumors. Recent studies have also indicated that curcumin can modulate the tumor immune response and remodel the tumor immunosuppressive microenvironment, indicating its potential in the immunotherapy of cancer. In this review, a brief introduction to the effects of curcumin on the tumor immune response and tumor immune microenvironment is provided and recent clinical trials investigating the potential of curcumin in cancer therapy are discussed.

Keywords: clinical trials; curcumin; cytotoxic T cells; immune response; natural killer cell; tumor suppressive immune environment.

Figure 1.

Curcumin exerts various effects on the malignant activities of tumor cells. Curcumin inhibits tumor cell proliferation through p21 or p27/CyclinD1/PI3K/Akt, JAK2/STAT3, Wnt/β-catenin and PI3K/Akt/mTOR signal pathways. Curcumin induces tumor cell apoptosis by mitochondria damage-mediated apoptosis, DNA self-repairing dysfunction and endoplasmic reticulum stress. Curcumin inhibits tumor cell EMT, which prevents tumor cell invasion and metastasis through downregulation of TGF-β expression and inactivation of TGF-β downstream signaling pathways. Neoangiogenesis is blocked by curcumin through decreasing the expression of VEGF and HGF, inactivating the PI3K/Akt/mTOR signaling pathway. Chemoresistance can be overcome by curcumin, which mediates cancer stem cell apoptosis. PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; JAK2, Janus kinase 2; STAT3, signal transducer and activator of transcription 3; mTOR, mammalian target of rapamycin; TGF-β1, tumor growth factor β1; ERK, extracellular regulated protein kinase; NF-κB, nuclear factor-κ-gene binding; EMT, epithelial-mesenchymal transition; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; HGF, hepatocyte growth factor.

Figure 2.

The three ‘E's of cancer immunoediting. (A) Elimination: IFN-γ, IL-12 and other tumor suppressive cytokines are released by NK cells and γδT cells mediate perforin, granzyme, FasL and TraiL-dependent cytotoxic effects in the early stage of tumor progression. Antigen-presenting cells present tumor-specific antigens to CD4+T cells, thereby recruiting specific CD8+ T cells to further kill tumor cells. (B) Equilibrium: Adaptive immunity prevents tumors from continuing to grow and confers immunogenicity to tumor cells to mediate immune recognition. Tumor cells can also block the constant immune system killing mechanism by gene mutations, which confer the ability of some tumor cells to escape from immune recognition. Therefore, tumor cells and the immune system reach an equilibrium state. (C) Escape: Tumor cells regulate the immune response of T cells and promote their apoptosis through releasing immunosuppressive cytokines, such as TGF-β and IL-10. In addition, increased intratumoral infiltration of CD4+CD25+FOXP3+Treg cells upregulates TGF-β and IL-10 expression levels and downregulates IL-2 expression levels. IFN, interferon; IL, interleukin; NK cells, natural killer cells; TGF-β, tumor growth factor β; Treg, regulatory T cell.

Figure 3.

The role of curcumin in tumor immunomodulation. The shaping of the tumor immunosuppressive microenvironment is induced by tumor cell secretion of immunosuppressive cytokines, such as IL-10 and TGF-β, apoptosis and malfunction of effector T cells and the infiltration of Treg cells. Curcumin remodels the tumor immunosuppressive microenvironment by: Regulating the infiltration of cytotoxic T cells and Treg by restoring NF-κB activity, inactivating the TNF-α signaling pathway; enhancing effector T cells function by elevating the expression of IFN-γ; modulating the function and expression of cytokines; increasing the generation of NK cells through impairment of the ubiquitin-proteasome system, activating STAT4, STAT5 and PI3K/Erk signaling pathway; and mediating the transformation of M2 TAMs into M1 TAMs. Treg, regulatory T cell; NK cells, natural killer cells; DCs, dendritic cells; TAM, Tumor-associated macrophage; TGF-β, Tumor growth factor β; IL, Interleukin; IFN, interferon.