Dendritic cell trafficking in tumor-bearing mice

Prostate cancer is one of the leading causes of cancer deaths, with no curative treatments once it spreads. Alternative therapies, including immunotherapy, have shown limited efficacy. Dendritic cells (DC) have been widely used in the treatment of various malignancies. DC capture antigens and move to the lymphoid organs where they prime naive T cells. Interaction between DC and T cells are most active in lymph nodes and suppression of DC trafficking to lymph nodes impairs the immune response. In this work, we aimed to study trafficking of DC in vivo via various routes of delivery, to optimize the effectiveness of DC-based therapy. A DC labeling system was developed using 1,1′-dioctadecyltetramethyl indotricarbocyanine Iodine for in vivo fluorescent imaging. DC harvested from C57B/6 mice were matured, labeled, and injected intravenously, subcutaneously, or intratumorally, with or without antigen loading with whole tumor lysate, into C57B/6 mice inoculated with RM-1 murine prostate tumor cells. Signal intensity was measured in vivo and ex vivo. Signal intensity at the tumor site increased over time, suggesting trafficking of DC to the tumor with all modes of injection. Subcutaneous injection showed preferential trafficking to lymph nodes and tumor. Intravenous injection showed trafficking to lungs, intestines, and spleen. Subcutaneous injection of DC pulsed with whole tumor lysate resulted in the highest increase in signal intensity at the tumor site and lymph nodes, suggesting subcutaneous injection of primed DC leads to highest preferential trafficking of DC to the immunocompetent organs.

[1]  B. Czerniecki,et al.  Optimizing Dendritic Cell-Based Approaches for Cancer Immunotherapy , 2014, The Yale journal of biology and medicine.

[2]  S. Rosenberg,et al.  Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  C. Rogers,et al.  Fuc-Tvii Is Required for T Helper 1 and T Cytotoxic 1 Lymphocyte Selectin Ligand Expression and Recruitment in Inflammation, and Together with Fuc-Tiv Regulates Naive T Cell Trafficking to Lymph Nodes , 2001, The Journal of experimental medicine.

[4]  Hua Wang,et al.  Adoptive cell transfer after chemotherapy enhances survival in patients with resectable HNSCC. , 2015, International immunopharmacology.

[5]  S. Rosenberg,et al.  Adoptive T-Cell Therapy for Cancer. , 2016, Advances in immunology.

[6]  Rajkumar Thangarajan,et al.  Dendritic cells primed with HPV positive cervical tumor lysate are superior to unprimed DCs in migratory capacity and induce a potent Th1 response. , 2014, Human immunology.

[7]  G. Sundaresan,et al.  Near-Infrared Imaging of Adoptive Immune Cell Therapy in Breast Cancer Model Using Cell Membrane Labeling , 2014, PloS one.

[8]  A. Larson,et al.  Antigen-loaded dendritic cell migration: MR imaging in a pancreatic carcinoma model. , 2015, Radiology.

[9]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[10]  Daniel A. Hammer,et al.  In Vivo Dendritic Cell Tracking Using Fluorescence Lifetime Imaging and Near-Infrared-Emissive Polymersomes , 2009, Molecular Imaging and Biology.

[11]  A. Sciarra,et al.  Beyond the Immune Suppression: The Immunotherapy in Prostate Cancer , 2015, BioMed research international.

[12]  Carl G. Figdor,et al.  Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting , 2007, Nature Reviews Immunology.

[13]  Melody A. Swartz,et al.  Dendritic-cell trafficking to lymph nodes through lymphatic vessels , 2005, Nature Reviews Immunology.

[14]  P. Allavena,et al.  In Vitro Studies on the Trafficking of Dendritic Cells Through Endothelial Cells and Extra-Cellular Matrix , 2000, Developmental immunology.

[15]  M. Gobbi,et al.  Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. , 1997, Journal of immunology.

[16]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[17]  T. Ezaki,et al.  Trafficking of host- and donor-derived dendritic cells in rat cardiac transplantation: allosensitization in the spleen and hepatic nodes. , 2001, Transplantation.

[18]  I. Treilleux,et al.  Regulation of the trafficking of tumour-infiltrating dendritic cells by chemokines. , 2004, Seminars in cancer biology.

[19]  L. Adorini,et al.  Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. , 2002, Human immunology.

[20]  E. Small,et al.  Sipuleucel-T (APC8015) for prostate cancer , 2006, Expert review of anticancer therapy.

[21]  S. Gambhir,et al.  Noninvasive cell-tracking methods , 2011, Nature Reviews Clinical Oncology.

[22]  M. Hellmich,et al.  Dendritic Cell Based Tumor Vaccination in Prostate and Renal Cell Cancer: A Systematic Review and Meta-Analysis , 2011, PloS one.

[23]  K. Anderson,et al.  Immunotherapy for the Treatment of Breast Cancer , 2015, Current Oncology Reports.

[24]  G. Coukos,et al.  Whole Tumor Antigen Vaccines: Where Are We? , 2015, Vaccines.

[25]  C. Caux,et al.  Dendritic cell biology and regulation of dendritic cell trafficking by chemokines , 2009, Springer Seminars in Immunopathology.

[26]  R. Komotar,et al.  Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme. , 2013, Cancer treatment reviews.

[27]  B. Haribabu,et al.  Regulation of dendritic cell migration and adaptive immune response by leukotriene B4 receptors: a role for LTB4 in up-regulation of CCR7 expression and function. , 2007, Blood.

[28]  Drew A. Torigian,et al.  A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside , 2013, Clinical Cancer Research.

[29]  Gang Wang,et al.  Intralymphatic Dendritic Cell Vaccination Induces Tumor Antigen–Specific, Skin-Homing T Lymphocytes , 2006, Clinical Cancer Research.

[30]  P. Dasgupta,et al.  Immunotherapy of prostate cancer: identification of new treatments and targets for therapy, and role of WAP domain-containing proteins. , 2011, Biochemical Society transactions.

[31]  I. Wicks,et al.  Different cross-presentation pathways in steady-state and inflammatory dendritic cells , 2009, Proceedings of the National Academy of Sciences.

[32]  Z. Berneman,et al.  Clinical use of dendritic cells for cancer therapy. , 2014, The Lancet. Oncology.

[33]  Karolina Palucka,et al.  Cancer immunotherapy via dendritic cells , 2012, Nature Reviews Cancer.

[34]  P. Kantoff,et al.  Immunotherapy for the treatment of prostate cancer , 2011, Nature Reviews Clinical Oncology.

[35]  H. Schild,et al.  Regulation of the tolerogenic function of steady‐state DCs , 2014, European journal of immunology.

[36]  Wen-Yuan Lee,et al.  Adjuvant immunotherapy with whole-cell lysate dendritic cells vaccine for glioblastoma multiforme: a phase II clinical trial. , 2012, World neurosurgery.

[37]  C. Huggins,et al.  STUDIES ON PROSTATIC CANCER: II. THE EFFECTS OF CASTRATION ON ADVANCED CARCINOMA OF THE PROSTATE GLAND , 1941 .

[38]  Michel Sadelain,et al.  In vivo imaging and quantitation of adoptively transferred human antigen-specific T cells transduced to express a human norepinephrine transporter gene. , 2007, Cancer research.

[39]  P. Ricciardi-Castagnoli,et al.  Dendritic cells at the end of the Millennium , 1999, Immunology and cell biology.

[40]  C. Demangel,et al.  Autocrine IL‐10 impairs dendritic cell (DC)‐derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL‐12 production , 2002, European journal of immunology.

[41]  Wei Zhu,et al.  Clinical outcome of immunotherapy with dendritic cell vaccine and cytokine-induced killer cell therapy in hepatobiliary and pancreatic cancer. , 2016, Molecular and clinical oncology.