Tumor Exosomes Inhibit Differentiation of Bone Marrow Dendritic Cells1

The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. In this study, we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b+ myeloid precursors in the bone marrow (BM) in vivo, and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block the differentiation of murine myeloid precursor cells into dendritic cells (DC) in vitro. Addition of tumor exosomes at day 0 led to a significant block of differentiation into DC, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited the differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after the tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of BM cells isolated from IL-6 knockout mice. Addition of a rIL-6 to the IL-6 knockout BM cell culture restored the tumor exosome-mediated inhibition of DC differentiation. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking BM DC differentiation.

[1]  D. Taylor,et al.  Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects , 2005, British Journal of Cancer.

[2]  Yuan Zhang,et al.  CD80 in immune suppression by mouse ovarian carcinoma-associated Gr-1+CD11b+ myeloid cells. , 2006, Cancer research.

[3]  W. Grizzle,et al.  A Membrane Form of TNF-α Presented by Exosomes Delays T Cell Activation-Induced Cell Death1 , 2006, The Journal of Immunology.

[4]  J. Cammenga,et al.  Gatekeeper pathways and cellular background in the pathogenesis and therapy of AML , 2005, Leukemia.

[5]  K. Heeg,et al.  Involvement of suppressors of cytokine signaling in toll-like receptor-mediated block of dendritic cell differentiation. , 2006, Blood.

[6]  F. Berthold,et al.  Gangliosides inhibit the development from monocytes to dendritic cells , 2002, Clinical and experimental immunology.

[7]  T. Whiteside,et al.  Tumour-derived exosomes or microvesicles: another mechanism of tumour escape from the host immune system? , 2005, British Journal of Cancer.

[8]  K. Syrigos,et al.  Serum levels of IL-6 and TNF-α correlate with clinicopathological features and patient survival in patients with prostate cancer , 2004, British Journal of Cancer.

[9]  B. Escudier,et al.  Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. , 2000, The cancer journal from Scientific American.

[10]  C. Divino,et al.  Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell anergy in tumor-bearing host. , 2006, Cancer research.

[11]  M. Neurath,et al.  Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer , 2005, Clinical reviews in allergy & immunology.

[12]  L. Zitvogel,et al.  Tumor-derived exosomes: a new source of tumor rejection antigens. , 2002, Vaccine.

[13]  A. Yoshimura,et al.  Suppression of IL-6 production and proliferation by blocking STAT3 activation in malignant soft tissue tumor cells. , 2006, Cancer letters.

[14]  P. Ferrari,et al.  Cell-mediated immunity in breast cancer patients. , 1996, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[15]  R. Kimberly,et al.  Cell type-specific glycoforms of Fc gamma RIIIa (CD16): differential ligand binding. , 1997, Journal of immunology.

[16]  María de Jesús Ibarra-Sánchez,et al.  Gr-1+ Myeloid Cells Lacking T Cell Protein Tyrosine Phosphatase Inhibit Lymphocyte Proliferation by an IFN-γ- and Nitric Oxide-Dependent Mechanism1 , 2003, The Journal of Immunology.

[17]  M. Büchler,et al.  High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. , 2005, Cancer research.

[18]  H. Lilja,et al.  Inhibition of dendropoiesis by tumor derived and purified prostate specific antigen. , 2003, The Journal of urology.

[19]  J. Ochoa,et al.  CD11b+/Gr-1+ Myeloid Suppressor Cells Cause T Cell Dysfunction after Traumatic Stress1 , 2006, The Journal of Immunology.

[20]  Kurt Zatloukal,et al.  Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. , 2005, Neoplasia.

[21]  W. Grizzle,et al.  A membrane form of TNFα presented by exosomes delays T cell activation-induced cell death. , 2006, The Journal of Immunology.

[22]  N. Horiike,et al.  Dendritic cells with immature phenotype and defective function in the peripheral blood from patients with hepatocellular carcinoma. , 1999, Journal of hepatology.

[23]  M. Colombo,et al.  Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity. , 2003, Blood.

[24]  William E. Grizzle,et al.  Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function1 , 2006, The Journal of Immunology.

[25]  D. Carbone,et al.  Tumor-host immune interactions and dendritic cell dysfunction. , 2004, Advances in cancer research.

[26]  R. Zeillinger,et al.  A Common Interleukin-6 Promoter Polymorphism in Patients With Vulvar Cancer , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[27]  J. Melo,et al.  Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration. , 2003, Blood.

[28]  J. Boulter,et al.  The Notch/Jagged Pathway Inhibits Proliferation of Human Hematopoietic Progenitors In Vitro , 1999, Stem cells.

[29]  D. Fuchs,et al.  Interleukin‐6 and oncostatin M stimulation of proliferation of prostate cancer 22Rv1 cells through the signaling pathways of p38 mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase , 2005, The Prostate.

[30]  M. Baccarani,et al.  Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6. , 2002, Blood.

[31]  D. Criddle,et al.  Endothelium‐dependent and ‐independent vasodilator effects of eugenol in the rat mesenteric vascular bed , 2003, The Journal of pharmacy and pharmacology.

[32]  A. Büssing,et al.  Release of interleukin-6 in cultured B-chronic lymphocytic leukaemia cells is associated with both activation and cell death via apoptosis. , 1999, Anticancer research.

[33]  M. D. Della Porta,et al.  Dendritic Cells and Vascular Endothelial Growth Factor in Colorectal Cancer: Correlations with Clinicobiological Findings , 2005, Oncology.

[34]  L. Zitvogel,et al.  Exosomes in cancer immunotherapy: preclinical data. , 2001, Advances in experimental medicine and biology.

[35]  J. Bourhis,et al.  NK cells differentiated from bone marrow, cord blood and peripheral blood stem cells exhibit similar phenotype and functions , 1998, European journal of immunology.

[36]  M. Neurath,et al.  IL-6 Signaling Promotes Tumor Growth in Colorectal Cancer , 2005, Cell cycle.

[37]  S. Segal,et al.  CD11b+/Gr-1+ Immature Myeloid Cells Mediate Suppression of T Cells in Mice Bearing Tumors of IL-1β-Secreting Cells1 , 2005, The Journal of Immunology.

[38]  A. Nicolini,et al.  Cytokines in breast cancer. , 2006, Cytokine & growth factor reviews.

[39]  K. Syrigos,et al.  Serum levels of IL-6 and TNF-α correlate with clinicopathological features and patient survival in patients with prostate cancer , 2004, British Journal of Cancer.

[40]  D. Carbone,et al.  VEGF as a mediator of tumor-associated immunodeficiency , 2001, Immunologic research.

[41]  D. Carbone,et al.  Clinical significance of defective dendritic cell differentiation in cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[42]  A. Lau,et al.  Dendritic cells and immune regulation in the liver , 2003, Gut.

[43]  Manuel E. Patarroyo,et al.  Expression of Adhesion Molecules CD 11/CD 18 (Leu-CAMs, β2-Integrins), CD54 (ICAM-1) and CD58 (LFA-3) in B -Chronic Lymphocytic Leukemia , 1994 .

[44]  D. Schmitt,et al.  Gangliosides from Human Melanoma Tumors Impair Dendritic Cell Differentiation from Monocytes and Induce Their Apoptosis , 2003, The Journal of Immunology.

[45]  M. Miñana,et al.  Selective Generation of Different Dendritic Cell Precursors from CD34+ Cells by Interleukin‐6 and Interleukin‐3 , 2004, Stem cells.

[46]  D. Gabrilovich,et al.  STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion1 , 2005, The Journal of Immunology.

[47]  W. Grizzle,et al.  BXD recombinant inbred mice represent a novel T cell–mediated immune response tumor model , 2002, International journal of cancer.