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Additional file 6: Fig. S1. Functional enrichment and network analysis in the TCGA-HNSC dataset. A Heatmap of the top 20 functional enrichment terms by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis based on differentially expressed therapeutic response-related genes (TRRGs). B Protein-protein interaction subnetworks of 20 functional enrichment terms.

Additional file 6: Fig. S1. Functional enrichment and network analysis in the TCGA-HNSC dataset. A Heatmap of the top 20 functional enrichment terms by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis based on differentially expressed therapeutic response-related genes (TRRGs). B Protein-protein interaction subnetworks of 20 functional enrichment terms.

Additional file 7: Fig. S2 Expression information of AREG, L1CAM and GPRC5D. A-C Kaplan Meier analysis showed that AREG, L1CAM and GPRC5D had a good prognostic efficacy in the Human Protein Atlas (HPA) database. D-F mRNA expression of AREG, L1CAM and GPRC5D was not significantly different between cancer and normal tissues in the TCGA database.

Additional file 7: Fig. S2 Expression information of AREG, L1CAM and GPRC5D. A-C Kaplan Meier analysis showed that AREG, L1CAM and GPRC5D had a good prognostic efficacy in the Human Protein Atlas (HPA) database. D-F mRNA expression of AREG, L1CAM and GPRC5D was not significantly different between cancer and normal tissues in the TCGA database.

Additional file 8: Fig. S3. Relationships between the risk score and immune checkpoint blockade (ICB)-associated genes and mutation rate. A ICB-associated genes and nonsilent mutation rate in the Risk-H and Risk-L groups. B Tumor purity, ESTIMATE score, immune score and stromal score in the Risk-H and Risk-L groups. ns, not significant; *, p < 0.05; **, p < 0.01; *** p < 0.001; ****, p< 0.0001.

Additional file 3: Supplementary Table S1. Comparison of RNF38 expression between nasopharyngeal carcinoma and normal nasopharyngeal epithelia tissues.

Additional file 1: Figure S1 Kaplan-Meier curves for OS of 131 patients with de novo metastatic NPC based on whether patients received RT to metastatic bone lesions or not that was divided by the cut-off values of 1 (a and b) and 3 bone metastases (c and d).

Additional file 2: Supplementary Table 1 Univariable and Multivariate analysis for OS in de novo mNPC patients classified by number of metastatic.

Additional file 5: Supplementary Table S3. Characteristics of patients with nasopharyngeal carcinoma grouped by RNF38 expression.

Huocong He*,1 Shuo Qie,*,2,3 Qiaojuan Guo,4 Shuyang Chen5,6 Changyan Zou,1 Tianzhu Lu,4 Ying Su,1 Jingfeng Zong,4 Hanchuan Xu,4 Dan He,5 Yun Xu,4 Bijuan Chen,4 Jianji Pan,4 Nianli Sang2,5 Shaojun Lin41Department of Radiation Biology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People’s Republic of China; 2Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA 19104, USA; 3Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA; 4Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University, Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, People’s Republic of China; 5Department of Biology, Drexel University College of Arts & Sciences, Philadelphia, PA 19104, USA; 6Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA*These authors contributed equally to this workBackground: Stanniocalcin 2 (STC2) expression is upregulated under multiple stress conditions including hypoxia, nutrient starvation and radiation. Overexpression of STC2 correlates with tumor progression and poor prognosis.Purpose: We previously demonstrated that overexpression of STC2 in nasopharyngeal carcinomas (NPC) positively correlates with radiation resistance and tumor metastasis, two major clinical obstacles to the improvement of NPC management. However, it remains elusive whether STC2 expression is a critical contributing factor for post-radiation survival and metastasis of NPC cells.Materials and methods: Using the radiation resistant CNE2 cell line as a model, we examined the importance of STC2 expression for post-radiation survival, migration and invasion. Here, we report the establishment of STC2 knockout lines (CNE2-STC2-KO) using the CRISPR/Cas9-based genome editing technique.Results: Compared with the parental line, STC2-KO cells showed similar proliferation and morphology in normal culture conditions, and loss of STC2 did not compromise the cell tumorigenicity in nude mice model. However, STC2-KO lines demonstrated increased sensitivity to X-radiation under either normoxic or hypoxic conditions. Particularly, upon X-radiation, parental CNE2 cells only slightly whereas STC2-KO cells remarkably decreased the migration and invasion ability. Cell cycle analysis revealed that loss of STC2 accumulated cells in G1 and G2/M phases but decreased S-population.Conclusion: These data indicate that the expression of STC2, which can be stimulated by metabolic or therapeutic stresses, is one important factor to promote survival and metastasis of post-radiation NPC cells. Therefore, targeting STC2 or relative downstream pathways may provide novel strategies to overcome radiation resistance and metastasis of NPC.Keywords: metabolic stress, metastasis, migration, nasopharyngeal carcinoma, radiation resistance, stanniocalcin 2

Background: The aberrant expression of surface receptors on immunocytes may represent potential markers of tumor escape for nasopharyngeal carcinoma (NPC). The aim of this study was to investigate the expression of representative receptors on natural killer (NK) cells and NK group 2, member D (NKG2D) on immunocytes in the peripheral blood of patients with NPC. Methods: Patients (n = 64) with NPC prior to initiation of treatment were defined as the study group. Healthy volunteers (n = 31) served as the control group. The expression of NK cells and NKT cells; the triggering receptors NKp30, NKp44, and NKp46 on NK cells; the activating receptor NKG2D on NK cells, CD4+ T cells, and CD8+ T cells; and the inhibitory receptors CD158b and CD159a on NK cells were analyzed by flow cytometry in the two groups. Results: Here, our study showed that no differences were observed in terms of the numbers of NK cells or NKT cells, or the expression of CD158b and CD159a on the surface of NK cells between the two groups. Nevertheless, the expression levels of NKp30 and NKp46 on NK cells in the NPC patients were significantly lower than in the healthy individuals (P < 0.05). No differences existed in the expression of NKG2D on NK cells, but NKG2D on CD8+ T cells showed a markedly lower expression in the study group (P < 0.001). Conclusions: Our findings may reflect a possible mechanism of immune evasion for NPC. The enhancement of immunotherapy concerning NKp30, NKp46, and NKG2D may be an innovative treatment strategy for patients with NPC.

BackgroundThis study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers.MethodsPatients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining.ResultsBetween August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and2 vs median 552.4 (IQR 258.4 to 1242.1) cells/mm2). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab.ConclusionsCamrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.

Tianzhu Lu,1,* Yiping Chen,2,* Jieyu Li,3 Qiaojuan Guo,2 Wansong Lin,3 Yuhong Zheng,4 Ying Su,5 Jingfeng Zong,2 Shaojun Lin,1,2 Yunbin Ye,3,6 Jianji Pan1,2 1The School of Clinical Medicine, Fujian Medical University, Fuzhou, People’s Republic of China; 2Department of Radiation Oncology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 3Laboratory of Immuno-Oncology, Fujian Cancer Hospital, Fuzhou, People’s Republic of China; 4Department of Clinical Laboratory, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 5Department of Radiation Biology, Fujian Cancer Hospital, Fujian Medical University, Fuzhou, People’s Republic of China; 6The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianji PanThe School of Clinical Medicine, Fujian Medical University, Fuzhou, People’s Republic of ChinaTel +86 591-83638732Fax +86 591-83928767Email panjianji1956@fjmu.edu.cnYunbin YeThe School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350014, People’s Republic of ChinaTel +86 591-83638732Fax +86 591-83928767Email zjyunbin@sina.comPurpose: Immune checkpoint proteins in the tumor microenvironment can enter the blood circulation and are potential markers for liquid biopsy. The aims of this study were to explore differences in immune checkpoint protein expression between patients with nasopharyngeal carcinoma (NPC) and healthy controls and to investigate the prognostic value of the soluble form of programmed death-ligand 1 (sPD-L1) in NPC.Methods: In total, 242 patients were included in the disease group. Plasma samples from 23 NPC patients and 15 healthy control were used for immune checkpoint protein panel assays. Samples from 219 patients with NPC including 30 paired pre-treatment and post-radiotherapy samples were evaluated by enzyme-linked immunosorbent assay to determine sPD-L1 levels.Results: A total of 14 immune checkpoint proteins, including sPD-L1were upregulated in 23 patients with NPC (all p< 0.001) compared with 15 healthy controls. Among 219 patients, the median follow-up time was 50 months (7– 82 months). Based on the optimal cutoff value of 93.7 pg/mL, patients with high expression of sPD-L1 had worse distant metastasis-free survival (87.5% vs 74.0%, p=0.006) than those of patients with low expression. Multivariate analysis showed that sPD-L1 (HR=1.99, p=0.048) and EBV-DNA (HR=2.51, p=0.030) were poor prognostic factors for DMFS. In the group with high EBV-DNA expression, DMFS was worse for patients with high sPD-L1 expression than those with low sPD-L1 expression (56.4% vs 82.6%, p=0.002).Conclusion: Plasma immune checkpoint protein expression differed significantly between patients with NPC and healthy donors. Plasma sPD-L1 levels are a candidate prognostic biomarker, especially when combined with EBV-DNA.Keywords: nasopharyngeal carcinoma, programmed death-ligand 1, Epstein-Barr virus, immune checkpoint protein

He H, Qie S, Guo Q, et al. Cancer Manag Res. 2019;11:6411–6424.On page 6421, Figure 7C. It was brought to the authors attention that a control micrograph was inadvertently placed into the experimental group in Figure 7 panel C during figure preparation. The authors have re-checked the original records and data analysis process and determined that the general conclusion of the study was not affected by this error. The authors apologize for this error.Read the original article&nbsp

Jinyi Lang*,1 Chaosu Hu*,2 Taixiang Lu,3 Jianji Pan,4 Tongyu Lin51Department of Radiation Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 3Department of Radiation Oncology, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China; 4Department of Radiation Oncology, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, People’s Republic of China; 5Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, and Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workAbstract: Nasopharyngeal carcinoma (NPC) is a rare type of head and neck cancer, with a higher incidence reported only in Southeast Asia and Northern Africa. Owing to the rarity of NPC occurrence, no internationally accepted consensus or guideline for its diagnosis and treatment is available. Based on the current evidences and practices, the Chinese experts on multidisciplinary diagnosis and treatment of NPC were designated to develop a national consensus for the treatment strategy of NPC. In this consensus, we report the development for improving the treatment efficacy and quality of life of NPC patients in China. The consensus also describes and recommends the role of multidisciplinary management approach in the management of NPC. A multidisciplinary team should include experts from different domains who can cater to the individualized needs of patients with NPC in a much more efficient manner. In addition, the team may also play a key role in developing guiding principles for future research, contributing to the improvement in the management of NPC.Keywords: Asian, Chinese, consensus, nasopharyngeal carcinoma, radiotherapy

The intracellularly-grown-Au-nanoparticles (IGAuNs) technique was employed to analyze the surface-enhanced Raman scattering (SERS) spectra of nasopharyngeal carcinoma cells (CNE-1 cell line). There are only six obvious Raman bands (718, 1001, 1123, 1336, 1446, 1660 cm−1) in the normal Raman spectrum of living CNE-1 cells. However, over twenty SERS Raman bands have been detected in the SERS spectra of IGAuNs-induced cells, among which five bands are of the DNA backbone (673, 1097, 1306, 1336 and 1585 cm−1). There are four vibrations of the DNA backbone (1026, 1097, 1336 and 1585 cm−1) in the SERS spectra of living CNE-1 cells induced by the passive uptake gold nanoparticles (PUAuNS), but one more DNA backbone and many nucleus Raman peaks appeared in the IGAuNs-induced SERS spectra. Many Raman peaks in the PUAuNs-induced SERS spectra are stronger than those in the IGAuNs-induced ones. This study has shown that the PUAuNs technique can achieve stronger Raman signals, and that the IGAuNs technique can enable the gold element to access to the nucleus more easily, which could help to obtain more surface-enhanced Raman signals of the intracellular biochemical molecules. Thus, the two techniques can work together to attain the Raman spectral information of the cytoplasm and the nucleus in a better way, which might provide a sensitive method for broad biomedical applications such as intracellular SERS analysis of living cells.

In this study, we examine the effects of recombinant adenovirus-p53 (rAd-p53) on the pancreatic carcinoma cell line SW1990. Specifically, we determine if expression of rAd-p53 sensitizes these cells to radiation.Following transfection of SW1990 cells with rAd-p53, we measured expression of P53, P21 and Bax by immunocytochemistry. Both transfected and control cell lines were irradiated with a range of doses, and the survival fractions (SF) were calculated. Dose survival curves were constructed and modeled for comparison.Transfection of SW1990 cells with rAd-p53 resulted in increased expression of P53, P21 and Bax in a time-dependent manner. At 96 h after transfection, 89.92% of cells expressed P53, 56.8% expressed P21, and 76.50% expressed Bax. The SF following radiation was lower in the rAd-p53 transfected cells compared to the control cells, suggesting that rAd-p53 sensitizes SW1990 cells to radiation (D0 for the experimental and control groups was 2.199 and 2.462, respectively).Use of the adenoviral vector is an effective means of transfecting SW1990 cells with wild-type P53, and this sensitizes the cell line to irradiation. This work suggests that combining rAd-p53 with radiation therapy in pancreatic cancer may be therapeutically beneficial.