Qiu Yan Chen

Emerging treatment options for nasopharyngeal carcinoma

Nasopharyngeal carcinoma is endemic in Asia and is etiologically associated with Epstein–Barr virus. Radiotherapy is the primary treatment modality. The role of systemic therapy has become more prominent. Based on multiple phase III studies and meta-analyses, concurrent cisplatin-based chemoradiotherapy is the current standard of care for locally advanced disease (American Joint Committee on Cancer manual [7th edition] stages II–IVb). The reported failure-free survival rates from phase II trials are encouraging for induction + concurrent chemoradiotherapy. Data from ongoing phase III trials comparing induction + concurrent chemoradiotherapy with concurrent chemoradiotherapy will validate the results of these phase II studies. Intensity-modulated radiotherapy techniques are recommended if the resources are available. Locoregional control exceeding 90% and reduced xerostomia-related toxicities can now be achieved using intensity-modulated radiotherapy, although distant control remains the most pressing research problem. The promising results of targeted therapy and Epstein–Barr virus-specific immunotherapy from early clinical trials should be validated in phase III clinical trials. New technology, more effective and less toxic chemotherapy regimens, and targeted therapy offer new opportunities for treating nasopharyngeal carcinoma.

Prospective Study of Tailoring Whole-Body Dual-Modality [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography With Plasma Epstein-Barr Virus DNA for Detecting Distant Metastasis in Endemic Nasopharyngeal Carcinoma at Initial Staging

PURPOSE To evaluate which patients with nasopharyngeal carcinoma (NPC) obtained the greatest benefits from the detection of distant metastasis with [(18)F]fluorodeoxyglucose positron emission tomography and computed tomography (PET/CT) combined with plasma Epstein-Barr virus (EBV) DNA levels. PATIENTS AND METHODS Consecutive patients with NPC were prospectively enrolled. PET/CT, conventional work-up (CWU), and quantification of plasma EBV DNA were performed before treatment. The accuracy of these strategies for distant metastases was assessed. The costs of the diagnostic strategies were compared. RESULTS Eighty-six (14.8%) of the 583 eligible patients were found to have distant metastases; 71 patients (82.6%) by PET/CT and 31 patients (36.0%) by CWU. In the multivariable analysis, advanced N stage (odds ratio, 2.689; 95% CI, 1.894 to 3.818) and pretreatment EBV DNA level (odds ratio, 3.344; 95% CI, 1.825 to 6.126) were significant risk factors for distant metastases. PET/CT was not superior to CWU for detecting distant metastases in very low-risk patients (N0-1 with EBV DNA < 4,000 copies/mL; P = .062), but was superior for the low-risk patients (N0-1 with EBV DNA ≥ 4,000 copies/mL and N2-3 with EBV DNA < 4,000 copies/mL; P = .039) and intermediate-risk patients (N2-3 disease with EBV DNA ≥ 4,000 copies/mL; P < .001). The corresponding patient management changes based on PET/CT were 2.9%, 6.3%, and 16.5%, respectively. The costs per true-positive case detected by PET/CT among these groups were ¥324,138 (≈

Tumor Microenvironment Macrophage Inhibitory Factor Directs the Accumulation of Interleukin-17-producing Tumor-infiltrating Lymphocytes and Predicts Favorable Survival in Nasopharyngeal Carcinoma Patients

47,458), ¥96,907 (≈

Distribution, characterization, and induction of CD8+ regulatory T cells and IL-17-producing CD8+ T cells in nasopharyngeal carcinoma

14,188), and ¥34,182 (≈

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

5,005), respectively. CONCLUSION PET/CT detects more distant metastases than conventional staging in patients with NPC. The largest benefit in terms of cost and patient management was observed in the subgroup with N2-3 disease and EBV DNA ≥ 4,000 copies/mL.

Exosomal miR-24-3p impedes T-cell function by targeting FGF11 and serves as a potential prognostic biomarker for nasopharyngeal carcinoma

Background: Tumor microenvironments affect the progression of cancers. Results: We demonstrated that Th17 cells were accumulated in tumor tissues, and the tumor-derived MIF induced Th17 cell accumulation and had clinical relevance in NPC. Conclusion: The cytokine MIF regulates intratumoral Th17 cell expansion and has prognostic value for NPC patients. Significance: The tumor microenvironment influences the clinical prognosis of NPC patients. The accumulation of an intratumoral CD4+ interleukin-17-producing subset (Th17) of tumor-infiltrating lymphocytes (TILs) is a general characteristic in many cancers. The relationship between the percentage of Th17 cells and clinical prognosis differs among cancers. The mechanism responsible for the increasing percentage of such cells in NPC is still unknown, as is their biological function. Here, our data showed an increase of Th17 cells in tumor tissues relative to their numbers in normal nasopharynx tissues or in the matched peripheral blood of NPC patients. Th17 cells in tumor tissue produced more IFNγ than did those in the peripheral blood of matched NPC patients and healthy controls. We observed high levels of CD154, G-CSF, CXCL1, IL-6, IL-8, and macrophage inhibitory factor (MIF) out of 36 cytokines examined in tumor tissue cultures. MIF promoted the generation and recruitment of Th17 cells mediated by NPC tumor cells in vitro; this promoting effect was mainly dependent on the mammalian target of rapamycin pathway and was mediated by the MIF-CXCR4 axis. Finally, the expression level of MIF in tumor cells and in TILs was positively correlated in NPC tumor tissues, and the frequency of MIF-positive TILs was positively correlated with NPC patient clinical outcomes. Taken together, our findings illustrate that tumor-derived MIF can affect patient prognosis, which might be related to the increase of Th17 cells in the NPC tumor microenvironment.

A randomized trial of induction chemotherapy plus concurrent chemoradiotherapy versus induction chemotherapy plus radiotherapy for locoregionally advanced nasopharyngeal carcinoma

BackgroundCD8+ effector cells often have an antitumor function in patients with cancer. However, CD8+Foxp3+ regulatory T cells (Tcregs) and interleukin (IL)-17-producing CD8+ T cells (Tc17 cells) also derive from the CD8+ T cell lineage. Their role in the antitumor response remains largely unknown. In the present study, we aimed to investigate the distribution, characterization, and generation of CD8+ Tcregs and Tc17 cells in NPC patients.MethodsPeripheral blood and tumor biopsy tissues from 21 newly diagnosed patients with nasopharyngeal carcinoma (NPC) were collected, along with peripheral blood from 21 healthy donors. The biological characteristics of Tcregs and Tc17 cells from blood and tumor tissues were examined by intracellular staining, tetramer staining and fluorescence-activated cell sorting (FACS) analysis. The suppressive function of Tcregs was investigated using a proliferation assay that involved co-culture of sorted CD8+CD25+ T cells with naïve CD4+ T cells in vitro.ResultsWe observed an increased prevalence of Tcregs and Tc17 cells among tumor-infiltrating lymphocytes (TILs) and different distribution among peripheral blood mononuclear cells (PBMCs) in NPC patients. Cytokine profiles showed that the Tcregs expressed a high level of IL-10 and low level of transforming growth factor β, whereas Tc17 cells expressed a high level of tumor necrosis factor α. Interestingly, both subsets expressed a high level of interferon γ in TILs, and the Tcregs suppressed naïve CD4+ T cell proliferation by a cell contact-dependent mechanism in vitro. Moreover, we demonstrated the existence of Epstein-Barr virus latent membrane protein (LMP) 1 and LMP2 antigen-specific Tcregs in NPC.ConclusionsOur data provide new insights into the composition and function of CD8+ T-cell subsets in NPC, which may have an important influence on NPC immunotherapy.

Establishment and Validation of Prognostic Nomograms for Endemic Nasopharyngeal Carcinoma

To understand the role of Epstein-Barr virus (EBV) and viral products in associated with immunophenotype and clinical outcome of primary nasopharyngeal carcinoma (NPC), the expression levels of chemokines IFN-γ-induced protein 10 (IP-10, CXCL10), stromal-derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 was investigated in 56 primary NPC biopsy specimens from Chinese NPC patients in parallels with LMP1 antigen and EBER1 by immunohistochemisty (IHC) and in situ hybridization (ISH). Moreover, the expression levels of HLA class I (β-microglobulin) and II antigen (HLA-DR), and co-stimulatory molecule CD54 were also evaluated in 31 out of these 56 patients using immunohistochemisty (IHC). Our results showed that (a) the elevated expression levels of IP10, SDF-1, CXCR4, β-microglobulin, HLA-DR, and CD54 in NPC lesions was 66%, 36%, 30%, 42%, 55% and 69%, respectively. (b) High expression of SDF-1 was observed in advanced NPC (N stage, P

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

Recent studies have shown that extracellular microRNAs are not only potential biomarkers but are also involved in cell interactions to regulate the intercommunication between cancer cells and their microenvironments in various types of malignancies. In this study, we isolated exosomes from nasopharyngeal carcinoma (NPC) cell lines and patient sera (T‐EXOs), or control NP69 cells and healthy donor sera (HD‐EXOs). We found that miR‐24‐3p was markedly enriched in T‐EXOs as compared with HD‐EXOs; the serum exosomal miR‐24‐3p level was correlated with worse disease‐free survival of patients (p < 0.05). Knockdown of exosomal miR‐24‐3p (miR‐24‐3p‐sponge‐T‐EXOs) by a sponge RNA targeting miR‐24‐3p restored the T‐EXO‐mediated (control‐sponge‐T‐EXO) inhibition of T‐cell proliferation and Th1 and Th17 differentiation, and the induction of regulatory T cells (Tregs). Mechanistic analyses revealed that administration of exosomal miR‐24‐3p increased P‐ERK, P‐STAT1 and P‐STAT3 expression while decreasing P‐STAT5 expression during T‐cell proliferation and differentiation. Moreover, by in vivo and in vitro assessments, we found FGF11 to be a direct target of miR‐24‐3p. However, both miR‐24‐3p‐sponge‐T‐EXOs and T‐EXOs (control‐sponge‐T‐EXOs) impeded proliferation and Th1 and Th17 differentiation, but induced Treg differentiation, of lenti‐shFGF11‐transfected T cells. The levels of phosphorylated ERK and STAT proteins were different in lenti‐ScshRNA‐transfected T cells and lenti‐shFGF11‐transfected T cells following administration of miR‐24‐3p‐sponge‐T‐EXO. Interestingly, tumour FGF11 expression was positively correlated with the number of CD4+ and CD8+ T cells in vivo, and predicted favourable patient DFS (p < 0.05). Additionally, hypoxia increased cellular and exosomal miR‐24‐3p levels and enhanced the inhibitory effect of T‐EXO on T‐cell proliferation and differentiation. Collectively, our findings suggest that exosomal miR‐24‐3p is involved in tumour pathogenesis by mediating T‐cell suppression via repression of FGF11, and may serve as a potential prognostic biomarker in NPC. Copyright

Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma

The aim of this randomized study was to compare the efficacy of induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) versus induction chemotherapy plus radiotherapy (IC+RT) for patients with locoregionally advanced nasopharyngeal carcinoma. From August 2002 to April 2005, 408 patients were randomly divided into two groups: an IC+CCRT group and an IC+RT group. Patients in both groups received the same induction chemotherapy: two cycles of floxuridine (FuDR)+carboplatin (FuDR, 750 mg/m(2), d1-5; carboplatin, area under the curve [AUC]=6). The patients received radiotherapy 1 week after they finished the induction chemotherapy. The patients in the IC+CCRT group also received carboplatin (AUC=6) on days 7, 28, and 49 of radiotherapy. Eight patients did not meet the inclusion criteria, and the remaining 400 cases were analyzed. Grade III or IV toxicity was found in 28.4% of the patients in the IC+CCRT group and 13.1% of those in the IC+RT group (P<.001). Five-year overall survival rates were 70.3% and 71.7% (P=0.734) in the IC+CCRT and IC+RT groups, respectively. No significant differences in failure-free survival, locoregional control, and distant control were found between the two groups. Compared with the IC+RT program, the IC+CCRT program used in the present study did not improve the overall survival and failure-free survival in patients with locoregionally advanced nasopharyngeal carcinoma. Using carboplatin in the concurrent chemoradiotherapy was not suitable for nasopharyngeal carcinoma.