Chemokine Signals in Head and Neck Cancer Progression

Summary

Principal Investigator: Robert Ferris
Affiliation: National Cancer Institute
Country: USA
Abstract: [unreadable] DESCRIPTION (provided by applicant): Chemokines are small molecules secreted by cells at inflammatory sites that mediate homing and recruitment of immune cells, through G-protein linked receptors. Recently, tumor cells have been shown to express chemokine receptor (CCR)7 that may facilitate lymph node metastasis, and we have shown upregulation of functional CCR7 on metastatic squamous cell carcinoma of the head and neck (SCCHN), compared to nonmetastatic tumors. Our data suggest that NF-?B mediates downstream CCR7-induced activities, as well as the expression of CCR7, itself, and its ligands in an autocrine loop. However, the mechanism and functional importance of CCR7 upregulation in vivo are not well understood. Our central hypotheses are that i) inflammatory signals in the tumor microenvironment lead to upregulation and activation of CCR7 by SCCHN cells, and ii) CCR7-mediated signals promote tumor progression, survival and metastasis. To test these hypotheses, in AIM 1 the effect of inflammatory autocrine/paracrine cytokines on CCR7 expression and activation of NF-?B will be analyzed in SCCHN cells, and the prognostic value of CCR7 expression as a biomarker of clinical disease status in SCCHN specimens will be analyzed by immunohistochemistry. AIM 2, we will elucidate the intracellular CCR7-mediated signals promoting invasion, survival and cis-platinum resistance of metastatic SCCHN cells. Because inhibition of a single signaling pathway is unlikely to have significant clinical benefit, combination targeting strategies are needed. Thus, the antitumor effect of CCR7 inhibition will be evaluated in vitro, and combined with another important signaling pathway in SCCHN, EGFR, to enhance the translational therapeutic potential. In AIM 3, the importance CCR7 activity on tumor progression in vivo will be tested in preclinical murine SCCHN model systems. We have observed that CCR7 overexpression increased migratory capacity of a poorly metastatic murine SCCHN tumor cell line. Using this model, the antitumor efficacy of CCR7 inhibition, in modulating tumor growth and metastasis will be tested alone or in combination with EGFR blockade. These data will be compared to tumor formation in plt/plt mice, which are deficient in CCR7 ligands. Overall these studies are designed to identify the EGFR-independent, CCR7-mediated pathways relevant to invasion and survival of SCCHN and to use this information to facilitate the development of CCR7 targeted therapeutic strategies. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-04-21 - 2011-02-28
more information: NIH RePORT

Top Publications

  1. pmc TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells
    Ryan M Stephenson
    Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
    Cancer Immunol Immunother 62:1347-57. 2013
  2. pmc The immune signature of CD8(+)CCR7(+) T cells in the peripheral circulation associates with disease recurrence in patients with HNSCC
    Malgorzata Czystowska
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Clin Cancer Res 19:889-99. 2013
  3. pmc Human beta-defensin 3 induces maturation of human langerhans cell-like dendritic cells: an antimicrobial peptide that functions as an endogenous adjuvant
    Laura K Ferris
    Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    J Invest Dermatol 133:460-8. 2013
  4. pmc Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread
    Robert L Ferris
    Hillman Cancer Center Research, Pavilion 5117 Centre Avenue, Room 2 26b, Pittsburgh, PA 15213, USA
    Clin Exp Metastasis 29:729-36. 2012
  5. pmc Chemokine receptor 7 (CCR7) gene expression is regulated by NF-κB and activator protein 1 (AP1) in metastatic squamous cell carcinoma of head and neck (SCCHN)
    Yvonne K Mburu
    Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 287:3581-90. 2012
  6. pmc Human β-defensin 3 promotes NF-κB-mediated CCR7 expression and anti-apoptotic signals in squamous cell carcinoma of the head and neck
    Yvonne K Mburu
    Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Carcinogenesis 32:168-74. 2011
  7. pmc Evaluation of a thyroid nodule
    Steven R Bomeli
    Division of Head and Neck Surgery, Department of Otolaryngology, University of Pittsburgh, PA, USA
    Otolaryngol Clin North Am 43:229-38, vii. 2010
  8. doi Recurrence in head and neck squamous cell carcinoma. Editorial
    Michael S Leibowitz
    Cancer 113:671-3. 2008
  9. doi Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy
    Jun Wang
    Department of Otolaryngology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
    J Natl Cancer Inst 100:502-12. 2008
  10. ncbi Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling
    Faina Linkov
    Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Cancer Epidemiol Biomarkers Prev 16:102-7. 2007

Scientific Experts

  • Michael Shurin
  • Robert L Ferris
  • Yvonne K Mburu
  • Laura K Ferris
  • Malgorzata Czystowska
  • Ryan M Stephenson
  • William Gooding
  • Carter Van Waes
  • Steven R Bomeli
  • Raja R Seethala
  • Jun Wang
  • Michael S Leibowitz
  • Faina Linkov
  • Andres Lopez-Abaitero
  • Maura Matthews
  • Theresa L Whiteside
  • Eric R Fluharty
  • Robert Hershberg
  • Alicia R Mathers
  • Miroslaw J Szczepanski
  • Chwee Ming Lim
  • Louis D Falo
  • Jonas T Johnson
  • Adriana T Larregina
  • Gregory Dietsch
  • Lin Wang
  • David S B Hoon
  • William H Walker
  • Ann Marie Egloff
  • Stanley P L Leong
  • Michael T Lotze
  • Donald L Morton
  • Koji Abe
  • Saumendra N Sarkar
  • Shane O LeBeau
  • Qing Zhang
  • Hitoshi Hasegawa
  • Anna Lokshin
  • Brian Nolen
  • Zoya Yurkovetsky
  • Lyudmila Velikokhatnaya
  • William Bigbee
  • Adele Marrangoni
  • Jill Siegfried
  • Alex Lisovich
  • Matthew Winans

Detail Information

Publications12

  1. pmc TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells
    Ryan M Stephenson
    Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
    Cancer Immunol Immunother 62:1347-57. 2013
    ..We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcγR-bearing cells...
  2. pmc The immune signature of CD8(+)CCR7(+) T cells in the peripheral circulation associates with disease recurrence in patients with HNSCC
    Malgorzata Czystowska
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Clin Cancer Res 19:889-99. 2013
    ..The functional and clinical significance of this imbalance was investigated using peripheral blood of patients with squamous cell carcinoma of the head and neck (HNSCC)...
  3. pmc Human beta-defensin 3 induces maturation of human langerhans cell-like dendritic cells: an antimicrobial peptide that functions as an endogenous adjuvant
    Laura K Ferris
    Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
    J Invest Dermatol 133:460-8. 2013
    ..Thus, hBD3 contributes to the integration of innate and adaptive immune responses in the skin, and may be a useful adjuvant for skin immunization and an important factor in the pathophysiology of inflammatory skin diseases...
  4. pmc Lymphatics, lymph nodes and the immune system: barriers and gateways for cancer spread
    Robert L Ferris
    Hillman Cancer Center Research, Pavilion 5117 Centre Avenue, Room 2 26b, Pittsburgh, PA 15213, USA
    Clin Exp Metastasis 29:729-36. 2012
    ..We present novel immune targets in nodal metastases, the importance of the lymph node as a pre-metastatic niche, and immune-related proteins as biomarkers of metastasis...
  5. pmc Chemokine receptor 7 (CCR7) gene expression is regulated by NF-κB and activator protein 1 (AP1) in metastatic squamous cell carcinoma of head and neck (SCCHN)
    Yvonne K Mburu
    Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 287:3581-90. 2012
    ..As such, CCR7, NF-κB, and AP1 could be potentially useful therapeutic targets in controlling the progression and metastasis of SCCHN tumors...
  6. pmc Human β-defensin 3 promotes NF-κB-mediated CCR7 expression and anti-apoptotic signals in squamous cell carcinoma of the head and neck
    Yvonne K Mburu
    Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
    Carcinogenesis 32:168-74. 2011
    ..Our findings suggest that hBD3 represents a novel NF-κB-regulated mediator of CCR7 expression and anti-apoptotic pathways, which may be exploited by developing SCCHN tumors to enhance their survival and metastasis...
  7. pmc Evaluation of a thyroid nodule
    Steven R Bomeli
    Division of Head and Neck Surgery, Department of Otolaryngology, University of Pittsburgh, PA, USA
    Otolaryngol Clin North Am 43:229-38, vii. 2010
    ..Detecting malignancy preoperatively allows total thyroidectomy in a single operation without the need for frozen section or a second operation for completion of a thyroidectomy if malignancy is found during the initial thyroid lobectomy...
  8. doi Recurrence in head and neck squamous cell carcinoma. Editorial
    Michael S Leibowitz
    Cancer 113:671-3. 2008
  9. doi Autocrine and paracrine chemokine receptor 7 activation in head and neck cancer: implications for therapy
    Jun Wang
    Department of Otolaryngology, University of Pittsburgh Medical School, Pittsburgh, PA, USA
    J Natl Cancer Inst 100:502-12. 2008
    ..Constitutive prosurvival signaling by the phosphoinositide-3 kinase/Akt pathway has been observed in SCCHN cells independent of epidermal growth factor receptor (EGFR) signaling...
  10. ncbi Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling
    Faina Linkov
    Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    Cancer Epidemiol Biomarkers Prev 16:102-7. 2007
    ..The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer...
  11. ncbi Intratumoral cytokines/chemokines/growth factors and tumor infiltrating dendritic cells: friends or enemies?
    Michael R Shurin
    Department of Pathology, University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, PA 15213, USA
    Cancer Metastasis Rev 25:333-56. 2006
    ..This review is limited to discussing the role of intratumoral cytokine network in the understanding immunobiology of tumor-associated dendritic cells, which seems to possess different regulatory functions at the tumor site...