Curcumin Induces the Differentiation of Myeloid-Derived Suppressor Cells and Inhibits Their Interaction with Cancer Cells and Related Tumor Growth

Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumors and contribute to tumor growth, angiogenesis, and progression. In this study, we examined the effects of curcumin on the activation and differentiation of MDSCs, their interaction with human cancer cells, and related tumor growth. Treatment with curcumin in the diet or by intraperitoneal injection significantly inhibited tumorigenicity and tumor growth, decreased the percentages of MDSCs in the spleen, blood, and tumor tissues, reduced interleukin (IL)-6 levels in the serum and tumor tissues in a human gastric cancer xenograft model and a mouse colon cancer allograft model. Curcumin treatment significantly inhibited cell proliferation and colony formation of cancer cells and decreased the secretion of murine IL-6 by MDSCs in a coculture system. Curcumin treatment inhibited the expansion of MDSCs, the activation of Stat3 and NF-κB in MDSCs, and the secretion of IL-6 by MDSCs, when MDSCs were cultured in the presence of IL-1β, or with cancer cell- or myofibroblast-conditioned medium. Furthermore, curcumin treatment polarized MDSCs toward a M1-like phenotype with an increased expression of CCR7 and decreased expression of dectin 1 in vivo and in vitro. Our results show that curcumin inhibits the accumulation of MDSCs and their interaction with cancer cells and induces the differentiation of MDSCs. The induction of MDSC differentiation and inhibition of the interaction of MDSCs with cancer cells are potential strategies for cancer prevention and therapy. Cancer Prev Res; 5(2); 205–15. ©2011 AACR.

[1]  B. Chauffert,et al.  Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. , 2010, The Journal of clinical investigation.

[2]  W. Nacken,et al.  Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein , 2008, The Journal of experimental medicine.

[3]  R. Jove,et al.  Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer , 2004, The Journal of Immunology.

[4]  J. Leips,et al.  Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression1 , 2006, The Journal of Immunology.

[5]  B. Reitz,et al.  Combined Use of the JAK3 Inhibitor CP-690,550 with Mycophenolate Mofetil to Prevent Kidney Allograft Rejection in Nonhuman Primates , 2005, Transplantation.

[6]  G. Bhagat,et al.  Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. , 2008, Cancer cell.

[7]  J. O’Shea,et al.  A new modality for immunosuppression: targeting the JAK/STAT pathway , 2004, Nature Reviews Drug Discovery.

[8]  L. Kaiser,et al.  Gemcitabine Selectively Eliminates Splenic Gr-1+/CD11b+ Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity , 2005, Clinical Cancer Research.

[9]  Bharat B. Aggarwal,et al.  “Spicing Up” of the Immune System by Curcumin , 2007, Journal of Clinical Immunology.

[10]  Hua Yu,et al.  Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity , 2005, Nature Medicine.

[11]  L. Bergmann,et al.  Curcumin Inhibits Constitutive STAT3 Phosphorylation in Human Pancreatic Cancer Cell lines and Downregulation of Survivin/BIRC5 Gene Expression , 2009, Cancer investigation.

[12]  Hiroyuki Tomita,et al.  Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. , 2011, Cancer cell.

[13]  D. Carbone,et al.  Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis. , 2008, Cancer cell.

[14]  V. Seifert,et al.  Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway , 2010, Clinical Cancer Research.

[15]  R. Benya,et al.  Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia , 2011, Cancer Prevention Research.

[16]  J. O’Shea,et al.  New strategies for immunosuppression: interfering with cytokines by targeting the Jak/Stat pathway , 2005, Current opinion in rheumatology.

[17]  R. Ádány,et al.  Tumor‐infiltrating myeloid‐derived suppressor cells are pleiotropic‐inflamed monocytes/macrophages that bear M1‐ and M2‐type characteristics , 2008, Journal of leukocyte biology.

[18]  J. Baron,et al.  Curcumin Chemoprevention: The Long Road to Clinical Translation , 2011, Cancer Prevention Research.

[19]  D. Gilvary,et al.  A Novel Chemoimmunomodulating Property of Docetaxel: Suppression of Myeloid-Derived Suppressor Cells in Tumor Bearers , 2010, Clinical Cancer Research.

[20]  B. Aggarwal,et al.  Modification of Cysteine 179 of IκBα Kinase by Nimbolide Leads to Down-regulation of NF-κB-regulated Cell Survival and Proliferative Proteins and Sensitization of Tumor Cells to Chemotherapeutic Agents* , 2010, The Journal of Biological Chemistry.

[21]  B. Aggarwal,et al.  Inhibiting NF-κB activation by small molecules as a therapeutic strategy. , 2010, Biochimica et biophysica acta.

[22]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[23]  W. Grizzle,et al.  TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. , 2010, The American journal of pathology.

[24]  M. Karin,et al.  Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. , 2010, Cytokine & growth factor reviews.

[25]  J. Leips,et al.  Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. , 2007, Cancer research.

[26]  B. Aggarwal,et al.  Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients' PBMCs: potential role for STAT-3 and NF-kappaB signaling. , 2010, The Journal of investigative dermatology.

[27]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[28]  L. Xinjian,et al.  Effect of curcumin on immune function of mice , 2008, Journal of Huazhong University of Science and Technology [Medical Sciences].

[29]  V. Bronte,et al.  Myeloid-derived suppressor cell role in tumor-related inflammation. , 2008, Cancer letters.

[30]  B. Rini,et al.  Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. , 2010, Cancer research.

[31]  B. C. Wong,et al.  Gene therapy for colon cancer by adeno-associated viral vector-mediated transfer of survivin Cys84Ala mutant. , 2005, Gastroenterology.

[32]  B. Aggarwal,et al.  Oxidative stress, inflammation, and cancer: how are they linked? , 2010, Free radical biology & medicine.

[33]  J. Califano,et al.  Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function , 2006, The Journal of experimental medicine.

[34]  K. Clément,et al.  Krüppel-like factor 4 regulates macrophage polarization. , 2011, The Journal of clinical investigation.

[35]  Changguo Chen,et al.  Curcumin inhibits mitogen stimulated lymphocyte proliferation, NFkappaB activation, and IL-2 signaling. , 2003, The Journal of surgical research.

[36]  M. Yuen,et al.  Suppression of survivin expression inhibits in vivo tumorigenicity and angiogenesis in gastric cancer. , 2003, Cancer research.

[37]  B. Aggarwal,et al.  Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals , 2010, Cancer and Metastasis Reviews.

[38]  P. Sinha,et al.  Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. , 2007, Cancer research.

[39]  R. Figlin,et al.  Sunitinib inhibition of Stat3 induces renal cell carcinoma tumor cell apoptosis and reduces immunosuppressive cells. , 2009, Cancer research.

[40]  D. Gabrilovich,et al.  Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. , 2011, Trends in immunology.

[41]  M. Manns,et al.  Myeloid-derived suppressor cells in inflammatory bowel disease: a new immunoregulatory pathway. , 2008, Gastroenterology.

[42]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[43]  D. Gabrilovich,et al.  Antigen-Specific Inhibition of CD8+ T Cell Response by Immature Myeloid Cells in Cancer Is Mediated by Reactive Oxygen Species1 , 2004, The Journal of Immunology.

[44]  G. Caldito,et al.  Curcumin Inhibits Carcinogen and Nicotine-Induced Mammalian Target of Rapamycin Pathway Activation in Head and Neck Squamous Cell Carcinoma , 2010, Cancer Prevention Research.

[45]  J. Vincent,et al.  5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. , 2010, Cancer research.

[46]  S. Albelda,et al.  Cross-Talk between Myeloid-Derived Suppressor Cells and Macrophages Subverts Tumor Immunity toward a Type 2 Response1 , 2007, The Journal of Immunology.

[47]  G. Bhagat,et al.  Histamine deficiency promotes inflammation-associated carcinogenesis through reduced myeloid maturation and accumulation of CD11b+Ly6G+ immature myeloid cells , 2010, Nature Medicine.

[48]  J. Auwerx,et al.  PPARγ Ligands Switched High Fat Diet-Induced Macrophage M2b Polarization toward M2a Thereby Improving Intestinal Candida Elimination , 2010, PloS one.