Anti-tumor effects of human peripheral gammadelta T cells in a mouse tumor model

Peripheral gammadelta T cells derived from healthy donors were found to exhibit cytotoxicity against a variety of tumor cell lines in vitro, including CNE2, which was established from nasopharyngeal carcinoma (NPC). The anti-tumor effects were further studied in a mouse model. Control nude mice inoculated s.c. with 5 x 10(6) CNE2 cells regularly developed hypodermal tumors, which progressively increased in size, and animals had a mean survival of 35 +/- 3.4 days. Tumor growth was arrested and tumor size was reduced after animals were infused with 5 x 10(7) gammadelta T cells derived from a healthy donor. The anti-tumor effects were temporary, however, and tumor growth was resumed after about 1 week in a group of the animals that had been given a single dose of gammadelta T cells. In another group of animals given 2 doses of gammadelta cells 1 week apart, resumption of tumor growth was delayed for a further week. Mean survival of the 2 groups was increased to 61 +/- 15.7 and 74 +/- 12.9 days, respectively. Immunohistology revealed an accumulation of infused cells in tumors attended by focal tumor necrosis in specimens taken 2 days after infusion. Infiltrative cells virtually disappeared from tumor tissues 6 days after infusion, accompanied by increased mitotic indices of tumor cells. These temporal relationships suggested that the accumulation of infused gammadelta T cells in hypodermal tumors was responsible for the observed anti-tumor effects.     

Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours

Background:

Adoptive transfer of ex vivo expanded autologous Vγ9Vδ2 T cells may be of therapeutic benefit for cancer because of their potent direct cytotoxicity towards tumour cells, synergistic cytotoxicity when combined with aminobisphosphonates and enhancement of antibody-dependent cell-mediated cytotoxicity.

Methods:

To determine the feasibility and clinical safety of therapy with ex vivo expanded, activated Vγ9Vδ2 T cells in combination with zoledronate, we enrolled 18 subjects with advanced solid tumours into a phase I clinical study. Administered indium¹¹¹-oxine-labelled Vγ9Vδ2 T cells were tracked in a cohort of patients.

Results:

Administered Vγ9Vδ2 T cells had an activated effector memory phenotype, expressed chemokine receptors predictive of homing to peripheral tissues and were cytotoxic in vitro against tumour targets. Adoptively transferred Vγ9Vδ2 T cells trafficked predominantly to the lungs, liver and spleen and, in some patients, to metastatic tumour sites outside these organs. No dose-limiting toxicity was observed, but most patients progressed on study therapy. However, three patients administered Vγ9Vδ2 T cells while continuing previously ineffective therapy had disease responses, suggesting an additive effect.

Conclusion:

Therapy with aminobisphosphonate-activated Vγ9Vδ2 T cells is feasible and well tolerated, but therapeutic benefits appear only likely when used in combination with other therapies.     

V gamma 9 V delta 2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs--rituximab and trastuzumab

V gamma 9 V delta 2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of V gamma 9 V delta 2 T cells is an attractive proposition for cell based immunotherapy. V gamma 9 V delta 2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (Fc gamma RIII), which raises the possibility that V gamma 9 V delta 2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of V gamma 9 V delta 2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, V gamma 9 V delta 2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16(+)V gamma 9 V delta 2 T cell population. Our results show that CD16(+)V gamma 9 V delta 2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or V gamma 9 V delta 2 T cells alone. Combination therapy involving ex vivo expanded CD16(+)V gamma 9 V delta 2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy.     

Regulatory T cells in tumor immunity

Recent studies have revealed that Foxp3⁺CD25⁺CD4⁺ regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self‐tolerance, play critical roles for the control of antitumor immune responses. For example, a large number of Foxp3⁺Tregs infiltrate into tumors, and systemic removal of Foxp3⁺Tregs enhances natural as well as vaccine‐induced antitumor T‐cell responses. Tregs are recruited to tumor tissues via chemokines, such as CCL22 binding to CCR4 expressed by Tregs. They appear to expand and become activated in tumor tissues and in the draining lymph nodes by recognizing tumor‐associated antigens as well as normal self‐antigen expressed by tumor cells. These results indicate that cancer vaccines targeting tumor‐associated self‐antigens may potentially expand/activate Tregs and hamper effective antitumor immune responses, and that tumor immunity can therefore be enhanced by depleting Tregs, attenuating Treg suppressive function, or rendering effector T cells refractory to Treg‐mediated suppression. Recent attempts have indeed demonstrated that combinations of monoclonal antibodies capable of modulating Treg functions synergistically enhance antitumor activity and are more effective than a single monoclonal antibody therapy. Combination therapy targeting a variety of molecules expressed in antigen‐presenting cells, effector T cells and Tregs is envisaged to be a promising anticancer immunotherapy.     

Tumour-infiltrating gamma/delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma.

BACKGROUND: Significant progress has been made in understanding the molecular biology of ovarian carcinoma. Along with the molecular characteristics of cancer, the patient's response to the tumour may also contribute to survival; in particular, the effect of the immune system may play an important role on survival of cancer patients. PATIENTS AND METHODS: We analysed the CD3 positive tumour-infiltrating T cells and direct molecular assessment of T cell receptors (TCRs) gamma and beta in 95 advanced ovarian carcinomas. RESULTS: Gamma/delta T cells are statistically correlated with a brief disease-free interval (P=0.036). CD3 positive tumour-infiltrating T cells are correlated with a brief disease-free interval and with survival (P=0.004 and P=0.0001, respectively). CD3 positive tumour-infiltrating T cells are associated with clinical responsiveness to chemotherapy (P=0.003). CONCLUSIONS: Further studies are required to better understand the role of gamma/delta T cells in ovarian carcinoma, yet these data underline the importance of host immune response to cancer and the need to better study immune mechanisms to modulate the therapeutic treatment of cancer.     

Tumor-reactive CD8+ T-cell clones in patients after NY-ESO-1 peptide vaccination

A major objective of peptide vaccination is the induction of tumor-reactive CD8+ T-cells. We have shown that HLA-A2 positive cancer patients frequently develop an antigen-specific CD8+ T-cell response after vaccination with NY-ESO-1 peptides p157-165/p157-167. These T-cells are highly reactive with the peptides used for vaccination, but only rarely recognize HLA-matched, NY-ESO-1 expressing tumor cell lines. To address the apparent lack of tumor recognition of vaccine-induced CD8+ T-cell responses, we used autologous tumor cells for in vitro stimulation and expansion of pre- and postvaccine CD8+ T-cells. In contrast to standard presensitization methods with peptide-pulsed antigen-presenting cells, mixed lymphocyte tumor culture favored the selective expansion of low-frequency tumor-reactive T-cells. In four patients, we were able to demonstrate that antigen-specific and tumor-reactive T-cells are detectable and are indeed elicited as a result of NY-ESO-1 peptide vaccination. Further analyses of postvaccine antigen-specific T-cells at a clonal level show that vaccine-induced antigen-specific T-cells are heterogeneous in functional activity. These results suggest that the methods of immunomonitoring are critical to identify the proportion of tumor-reactive T-cells within the population of vaccine-induced antigen-specific effector cells. Our results show that immunization with NY-ESO-1 peptides leads to strong tumor-reactive CD8+ T-cell responses. Our findings suggest that approaches to peptide vaccination may be improved to induce higher numbers of antigen-specific T-cells and to selectively increase the proportion of CD8+ T-cells that have the capacity to recognize and eliminate tumor cells.     

Over‐expression of phosphatase of regenerating liver‐3 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma

This study aimed at clarifying the expression of phosphatase of regenerating liver‐3 (PRL‐3), one member of protein tyrosine phosphatase (PTP) superfamily, in nasopharyngeal carcinoma (NPC) and its correlation with clinicopathologic features, including the survival of patients with NPC. Real‐time PCR and Western blot showed that the expression level of PRL‐3 was markedly higher in NPC cell lines than that in the normal nasopharyngeal epithelial cell at both mRNA and protein levels. Immunohistochemical analysis revealed overexpression of PRL‐3 in 97 of 174 (55.7%) paraffin‐embedded archival NPC biopsies. Statistical analysis showed that PRL‐3 expression was positively correlated with N classification (p = 0.033), distant metastasis (M classification, p = 0.048) and clinical stage (p = 0.005) of patients. Patients with higher PRL‐3 expression had shorter overall survival time, whereas patients with lower level of PRL‐3 had better survival. Multivariate analysis suggested that PRL‐3 expression might be an independent prognostic indicator for the survival of patients with NPC. Disruption of endogenous PRL‐3 protein through a siRNA knockdown technique was shown to suppress the invasion ability and migration potency of 5‐8F and HONE1 cells, substantially. Interestingly, we also found that no significant effect on the proliferation of 5‐8F and HONE1 cells was observed after PRL‐3 was down‐regulated. Our results suggest that PRL‐3 protein is a valuable marker for progression of NPC patients. High PRL‐3 expression is associated with poor overall survival in patients with NPC. © 2008 Wiley‐Liss, Inc.     

Regulatory T-cell function of adult T-cell leukemia/lymphoma cells

Adult T-cell leukemia/lymphoma (ATLL) patients are highly immunocompromised, but the underlying mechanism responsible for this state remains obscure. Recent studies demonstrated that FOXP3, which is a master control gene of naturally occurring regulatory T (Treg) cells, is expressed in the tumor cells from a subset of patients with ATLL. Since most ATLL cells express both CD4 and CD25, these tumors might originate from CD4(+)CD25(+)FOXP3(+) Treg cells, based on their phenotypic characteristics. However, whether ATLL cells actually function as Treg cells has not yet been clearly demonstrated. Here, we show that ATLL cells from a subset of patients are not only hypo-responsive to T-cell receptor-mediated activation, but also suppress the proliferation of autologous CD4(+) non-ATLL cells. Furthermore, ATLL cells from this subset of patients secrete only small amounts of IFN-gamma, and suppress IFN-gamma production by autologous CD4(+) non-ATLL cells. These are the first data showing that ATLL cells from a subset of patients function as Treg cells in an autologous setting. The present study provides novel insights into understanding the immunopathogenesis of ATLL, i.e., how HTLV-1-infected cells can survive in the face of host immune responses. It also adds to our understanding of ATLL patients' severely immunocompromised state.     

The association between circulating tumor cells and Epstein-Barr virus activation in patients with nasopharyngeal carcinoma

Background: Circulating tumor cells (CTCs) and microemboli (CTM) are attracting increasing attention in medical biology and clinical practice. However, the clinical relevance of CTCs in nasopharyngeal carcinoma (NPC) has not yet been ascertained, and no study has focused on the influence of Epstein-Barr virus (EBV) status on CTCs in NPC patients. These issues were therefore examined. Methods: Peripheral blood samples were prospectively obtained from 33 NPC patients before treatment. CTCs and CTM were captured using the Isolation by Size of Epithelial Tumor (ISET) method. Immunohistochemistry on CK5/6 (cytokeratin5/6) and P63, as well as in situ hybridization of EBERs (EBV-encoded RNAs) were used to validate the harvested tumor cells. Results: Out of 33 NPC patients, CTCs were detected in 22 cases (66.7%), and CTM were observed in 2 cases (6.1%). CTCs were presented in all stages of NPC patients but had no association with the TNM stages (all P > 0.05). The presence of CTCs appeared to correlate with EBV activation status. Among the total NPC patients, the EBV VCA-IgA levels in CTC-positive cases were higher than that in CTC-negative cases (negative vs. positive: 3.88 vs. 4.86, P = 0.016). A similar result was observed in the patients without distant metastasis (negative vs. positive: 3.76 vs. 4.95, P = 0.009). When the number of CTCs was considered, CTC counts were found to correlate with EBV VCA-IgA (R = 0.382, P = 0.041) and EBV DNA load (R = 0.396, P = 0.033) for all NPC patients as well as NPC patients without distant metastases. Conclusions: These findings strongly suggested detectable CTCs/CTM in all stages of NPC patients and support a positive correlation between CTCs and EBV activation in NPC patients.     

Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy

Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gammadeltaT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gammadelta T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 microM ZOL plus IL-2 increased the absolute number of gammadeltaT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 microM ZOL showed a marked increase in sensitivity to lysis by gammadeltaT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gammadeltaT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 microg/kg ZOL also significantly enhanced the antitumor activity of gammadeltaT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gammadeltaT cells and that gammadeltaT cells required pre-treatment with ZOL for cytotoxic activity against target cells.     

Characterization of CACNA2D3 as a putative tumor suppressor gene in the development and progression of nasopharyngeal carcinoma

Apart from β‐catenin accumulation, loss of 3p21 is one of the most frequent genetic alterations in numerous malignancies including nasopharyngeal carcinoma (NPC). Herein, we characterized a novel candidate tumor suppressor gene (TSG) CACNA2D3, a voltage‐dependent subunit alpha 2 delta 3 of a calcium channel complex. Downregulation of CACNA2D3 was frequently detected in primary NPCs and NPC cell lines compared with their nontumorigenic counterparts. Attenuated CACNA2D3 expression may be associated with loss of heterozygosity (LOH) at intragenic single‐nucleotide polymorphism sites (rs589281, rs1449325 and rs6797113) and/or epigenetic silencing by methylation and histone deacetylation. Given the extensive effects of calcium in cancer, we then investigated the tumor suppressive role and underlying mechanism of CACNA2D3 in the development and progression of NPC. CACNA2D3 was stably transfected into NPC cell lines (C666 and SUNE1) at levels comparative with the normal nasopharynx, alongside siRNA‐mediated silencing in an immortalized nasopharyngeal epithelial cell line (NP69) to conduct in vivo and in vitro functional assays. Our findings show that CACNA2D3‐mediated increase in intracellular calcium (Ca2+) can induce mitochondrial‐mediated apoptosis and activation of NLK (through the Wnt/Ca2+ pathway) to antagonize Wnt signaling‐mediated anchorage‐dependent and independent cell proliferation (via CCND1 and CMYC), invasion (via MMP7) and epithelial‐to‐mesynchemal transition (via SNAIL). As the expression pattern of calcium channels and their degree of functionality can change with the progression of cancer, CACNA2D3 may indeed be a promising biomarker for NPC. Our study also warrants further exploration in the potential therapeutic use of existing epigenetic targeting drugs (e.g., 5‐azacytidine, SAHA) to reconstitute CACNA2D3‐associated tumor suppression in NPC.     

Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis

T-cell infiltration into human cancer tissues can be a manifestation of host immune responses to cancer cells. The present study was undertaken to explore the clinicopathological significance of intraepithelial CD8(+) T cells using 371 consecutively sampled human colorectal carcinomas. By univariate analysis, we noted that the survival curves by intraepithelial CD8(+) T cells became separated only after 1 to 2 years postoperation. Multivariate analyses revealed that the beneficial effect of this factor becomes significant only after a longer (more than 2 year), but not after a shorter (less than 2 year) follow-up period. Furthermore, the number of intraepithelial CD8(+) T cells was significantly higher in patients alive for more than 5 years than in patients who either died of cancer after a curative operation or patients who underwent a noncurative operation. Patients' cancer-specific death long after a curative operation is thought to be caused by the growth of micrometastases in other organs or near the primary sites. The effects of intraepithelial CD8(+) T cells, therefore, may be mediated by suppression of micrometastasis, rather than suppression of growth in the primary tumour. In conclusion, our data support a hypothesis on the presence of systemic immunosurveillance against micrometastasis of cancer cells.     

Expression of IL-27 in murine carcinoma cells produces antitumor effects and induces protective immunity in inoculated host animals

A novel cytokine interleukin-27 (IL-27), composed of p28 and Epstein-Barr virus-induced gene 3 (EBI3), is produced from activated dendritic cells and is involved in an early phase of T-helper type I differentiation. We examined whether Colon 26 murine colon carcinoma cells that were retrovirally transduced with the p28-linked EBI3 gene (Colon 26/IL-27) could produce antitumor effects in inoculated mice. Although proliferation in vitro of Colon 26/IL-27 cells was not different from that of parent cells, syngeneic BALB/c mice rejected Colon 26/IL-27 tumors inoculated and subsequently acquired tumor-specific protective immunity. In contrast, mice inoculated with Colon 26 cells transduced with either the p28 or EBI3 gene developed tumors and survival of the mice remained the same as that of the mice inoculated with parent cells. Syngeneic nude mice developed Colon 26/IL-27 tumors, but the growth was retarded compared to that of parent tumors. Depletion of natural killer cells from nude mice with anti-asialo GM(1) antibody diminished the growth retardation of Colon 26/IL-27 tumors. Survival of severe combined immunodeficient mice that received subcutaneous inoculation of Colon 26/IL-27 cells was not different from that of the immunodeficient mice inoculated with parent cells. Interferon-gamma was produced from CD4(+) and CD8(+) T, and natural killer cells of the mice that rejected Colon 26/IL-27 tumors and cytotoxic activity against Colon 26 cells were also detected from the mice. These data collectively suggest that expressed IL-27 in tumors produces T cell-dependent and-independent antitumor effects and is a possible therapeutic strategy for cancer.     

Suppression of 6A8 alpha-mannosidase gene expression reduced the potentiality of growth and metastasis of human nasopharyngeal carcinoma

Suppression of alpha-mannosidases by chemicals has been shown to reduce the potentiality of growth and metastasis of various tumors. In our study, the effect of 6A8 alpha-mannosidase (MAN 6A8), recently discovered in our laboratory, on malignant behaviors of tumor cells was examined. Since the suppressive effect of chemicals on alpha-mannosidase is not specific, antisense technique was used to specifically inhibit expression of the MAN 6A8 in human nasopharyngeal carcinoma cells, CNE-2L2. Two cell clones, AS1 and AS2, with pronounced suppression of MAN 6A8 expression were developed. Wild-type (W), mock-transduced (M) and irrelevant DNA-transduced (IR) CNE-2L2 cells with normal expression of the enzyme were used as controls. Malignant behaviors of the cells were examined. Significant inhibition of growth of AS cells in vitro measured by MTT assay, colony formation and anchorage-independent colony formation was found. Pronounced inhibition of formation of tumors from AS cells inoculated into nude mice and metastasis was also observed. W, M and IR cells cultured in plate wells appeared dispersed with a fibroblastic or epithelial morphology, whereas AS cells were in compact sheets with an epithelioid organization. Since E-cadherin is the key factor in homophilic adhesion of epithelial cells, its expression on the surface of CNE-2L2 cells was determined. E-cadherin expression on AS cells was enhanced, whereas it was markedly diminished on W, M and IR cells. In addition, lamellipodia, which play an important role in cell spreading and mobility, almost disappeared on AS cells. The results demonstrate a significant suppressive effect of reduced expression of MAN 6A8 on malignant behaviors of CNE-2L2 cells.     

alpha-Galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunity

Most of the current tumor vaccines successfully elicit strong protection against tumor but offer little therapeutic effect against existing tumors, highlighting the need for a more effective vaccine strategy. Vaccination with tumor antigen-presenting cells can induce antitumor immune responses. We have previously shown that NKT-licensed B cells prime cytotoxic T lymphocytes (CTLs) with epitope peptide and generate prophylactic/therapeutic antitumor effects. To extend our B cell vaccine approach to the whole antigen, and to overcome the MHC restriction, we used a nonreplicating adenovirus to transduce B cells with antigenic gene. Primary B cells transduced with an adenovirus-encoding truncated Her-2/neu (AdHM) efficiently expressed Her-2/neu. Compared with the moderate antitumor activity induced by vaccination with adenovirus-transduced B cells (B/AdHM), vaccination with alpha-galactosylceramide-loaded B/AdHM (B/AdHM/alpha GalCer) induced significantly stronger antitumor immunity, especially in the tumor-bearing mice. The depletion study showed that CD4(+), CD8(+) and NK cells were all necessary for the therapeutic immunity. Confirming the results of the depletion study, B/AdHM/alpha GalCer vaccination induced cytotoxic NK cell responses but B/AdHM did not. Vaccination with B/AdHM/alpha GalCer generated Her-2/neu-specific antibodies more efficiently than B/AdHM immunization. More importantly, B/AdHM/alpha GalCer could prime Her-2/neu-specific cytotoxic T cells more efficiently and durably than B/AdHM. CD4(+) cells appeared to be necessary for the induction of antibody and CTL responses. Our results demonstrate that, with the help of NKT cells, antigen-transduced B cells efficiently induce innate immunity as well as a wide range of adaptive immunity against the tumor, suggesting that they could be used to develop a novel cellular vaccine.     

Gamma delta T 细胞及其抗肿瘤研究的进展

Gamma delta（γδ）T细胞表达Vγ9Vδ2 T细胞受体,占外周血T淋巴细胞的2％～5％左右,主要分布于黏膜相关淋巴组织,是T细胞的亚群之一。其免疫作用介于固有免疫和适应性免疫之间,为主要组织相容性复合体（MHC）非限制性细胞, 具有一定的非特异性杀伤肿瘤细胞的作用,并且具有广泛的抗瘤谱。许多研究证实γδ T细胞参与了机体免疫防御系统的第一道防线,未来以γδ T细胞为基础的细胞免疫疗法,将会成为肿瘤免疫治疗的新战略。本文将对γδ T细胞的抗肿瘤作用机制及其临床应用作一综述。     

Multiple dysregulated pathways in nasopharyngeal carcinoma revealed by gene expression profiling

Gene expression profiling was conducted using primary human nasopharyngeal carcinoma (NPC) biopsy samples to improve the understanding of the molecular pathways defining NPC and to identify novel potential therapeutic targets. RNA samples were extracted from 36 patients suspected to have NPC and hybridized onto the Affymetrix U133A chip. NPC was diagnosed in 19 patients, 11 had lymphoid hyperplasia (LH), and 6 were "normal" biopsies. Clinical stages for these NPC patients ranged from I-IV, including one M1. All NPC patients (except the M1) were treated with curative intent, which included radiotherapy alone (4 patients), or combined with chemotherapy (14 patients). Unsupervised clustering demonstrated a distinct NPC expression pattern, compared to normal biopsies. Subsequent Significance Analysis of Microarrays (SAM) derived from 14 NPC and 6 normal samples discovered 1,089 differentially regulated genes. Pathway analyses revealed novel insights into the mechanisms leading to NPC, whereby upregulation of NFkappaB2 and survivin play central roles in increasing resistance to apoptosis, and changes in integrin and WNT/beta-catenin signaling leading to uncontrolled proliferation. The role of survivin in resisting apoptosis in NPC was confirmed by RNA interference. Our data provide novel insights into the development and progression of NPC, and suggest survivin as a novel therapeutic target for NPC.