Immunologic Consequences of Signal Transducers and Activators of Transcription 3 Activation in Human Squamous Cell Carcinoma

被引:19
作者
Albesiano, Emilia [2 ,3 ]
Davis, Meghan [1 ]
See, Alfred P. [4 ]
Han, James E. [4 ]
Lim, Michael [4 ]
Pardoll, Drew M. [2 ,3 ]
Kim, Young [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21231 USA
[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA
[3] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA
[4] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21231 USA
关键词
ENDOTHELIAL GROWTH-FACTOR; INDUCIBLE PROTEIN-10; STAT3; CANCER; INNATE; DIFFERENTIATION; MONOCYTES; CHEMOKINE; CYTOKINE; IMMUNITY;
D O I
10.1158/0008-5472.CAN-09-4058
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention. Cancer Res; 70(16); 6467-76. (C)2010 AACR.
引用
收藏
页码:6467 / 6476
页数:10
相关论文
共 39 条
  • [1] A critical role for stat3 signaling in immune tolerance
    Cheng, FD
    Wang, HW
    Cuenca, A
    Huang, M
    Ghansah, T
    Brayer, J
    Kerr, WG
    Takeda, K
    Akira, S
    Schoenberger, SP
    Yu, H
    Jove, R
    Sotomayor, EM
    [J]. IMMUNITY, 2003, 19 (03) : 425 - 436
  • [2] Validating Stat3 in cancer therapy
    Darnell, JE
    [J]. NATURE MEDICINE, 2005, 11 (06) : 595 - 596
  • [3] STATs and gene regulation
    Darnell, JE
    [J]. SCIENCE, 1997, 277 (5332) : 1630 - 1635
  • [4] Interleukin-6 predicts recurrence and survival among head and neck cancer patients
    Duffy, Sonia A.
    Taylor, Jeremy M. G.
    Terrell, Jeffrey E.
    Islam, Mozaffarul
    Li, Yun
    Fowler, Karen E.
    Wolf, Gregory T.
    Teknos, Theodoros N.
    [J]. CANCER, 2008, 113 (04) : 750 - 757
  • [5] DVORAK HF, 1986, NEW ENGL J MED, V315, P1650
  • [6] TNF-α and the IFN-γ-inducible protein 10 (IP-10/CXCL-10) delivered by parvoviral vectors act in synergy to induce antitumor effects in mouse glioblastoma
    Enderlin, M.
    Kleinmann, E. V.
    Struyf, S.
    Buracchi, C.
    Vecchi, A.
    Kinscherf, R.
    Kiessling, F.
    Paschek, S.
    Sozzani, S.
    Rommelaere, J.
    Cornelis, J. J.
    Van Damme, J.
    Dinsart, C.
    [J]. CANCER GENE THERAPY, 2009, 16 (02) : 149 - 160
  • [7] Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo
    Gabrilovich, D
    Ishida, T
    Oyama, T
    Ran, S
    Kravtsov, V
    Nadaf, S
    Carbone, DP
    [J]. BLOOD, 1998, 92 (11) : 4150 - 4166
  • [8] Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells
    Gabrilovich, DI
    Chen, HL
    Cunningham, HT
    Meny, GM
    Nadaf, S
    Kavanaugh, D
    Carbone, DP
    [J]. NATURE MEDICINE, 1996, 2 (10) : 1096 - 1103
  • [9] Gupta S, 2008, BIOL-TARGETS THER, V2, P707
  • [10] Abnormal stat activation, hematopoietic homeostasis, and innate immunity in c-fes-/- mice
    Hackenmiller, R
    Kim, J
    Feldman, RA
    Simon, MC
    [J]. IMMUNITY, 2000, 13 (03) : 397 - 407