Long-term outcomes after particle radiation therapy in patients with nasopharyngeal adenoid cystic carcinoma.

BACKGROUND: Nasopharyngeal adenoid cystic carcinoma (NACC) is a relatively rare salivary gland tumor that is generally associated with poor outcomes. High-dose radiotherapy is a key treatment for patients with NACC. This study reported the long-term efficacy and safety of particle beam radiation therapy (PBRT) for NACC. METHODS AND MATERIALS: Twenty-six patients with nonmetastatic NACC who received definitive PBRT alone were included in this retrospective study. The majority of patients (92.3%) had locally advanced disease. Twenty-five (96.15%) patients received intensity-modulated proton radiotherapy (IMPT) followed by a carbon ion radiotherapy (CIRT) boost, and one patient received CIRT alone. Overall survival (OS), local control (LC), regional control (RC), and distant metastasis control (DMC) rates were calculated via the Kaplan-Meier method. RESULTS: The median follow-up time was 46.95 months for the entire cohort. Seven patients experienced local recurrence, and one patient experience neck lymph node recurrence. The 3- and 4-year OS, LC, RC, and DMC rates were 100% and 91.7%, 92.3% and 84.6%, 95.8% and 87.8%, and 90.2% and 71.3%, respectively. A total of 91.3% of the patients achieved complete remission of gross tumors at 1 year after PBRT. Severe acute toxicity was observed in only two patients. A grade 4 decrease in visual acuity was observed in one patient with orbital apex invasion. No late grade 3 or 5 toxicity was observed. CONCLUSION: Definitive PBRT provided a satisfactory 4-year OS for patients with locally advanced NACC. The toxicity was acceptable and mild. Further follow-up is necessary to confirm the efficacy and safety of definitive PBRT for patients with NACC.

TRIB3 promotes malignancy of head and neck squamous cell carcinoma via inhibiting ferroptosis.

Tribbles pseudokinase 3 (TRIB3) has been identified recently as a novel oncogene in several cancers. Still, further extensive research is imperative to elucidate its function and the molecular mechanisms underlying its involvement in the progression of head and neck squamous cell carcinoma (HNSCC). In our study, we found that TRIB3 silencing significantly promoted cell death by inducing ferroptosis. The interaction of TRIB3 with Transcription Factor 4 (TCF4) and ß-catenin created a heterotrimeric complex, which directly interacts with the ALOXE3 promoter, detrimentally impacting its activation. The consequential partial neutralization of ferroptosis induced by TRIB3 deficiency is observed through the implementation of ALOXE3 knockdown. Furthermore, the study demonstrated that the molecular inhibitor hesperidin, targeting TRIB3, not only reduced cell malignancy but also induced ferroptosis, thereby suppressing tumor growth. Overall, our findings unequivocally validate the proposition that TRIB3 deficiency precipitates the iron death mechanism, thereby indicating that the strategic targeting of TRIB3 could emerge as an innovative therapeutic strategy for HNSCC.

Tumor volume instead of recurrent T category predicts clinical outcome of patients with locally recurrent nasopharyngeal carcinoma salvaged by carbon ion radiation therapy.

BACKGROUND: Although carbon ion radiation therapy (CIRT) substantially improves the overall survival (OS) of patients with LR-NPC, approximately 40% of the patients may develop local recurrence. The purpose of study is to assess the value of tumor volume (TV) as a predictive tool to guide individualized CIRT. METHODS: Consecutive patients with LR-NPC treated using CIRT at Shanghai Proton and Heavy Ion Center between April 2015 and May 2019 were included. TV before CIRT was delineated and calculated. The generalized additive Cox model was used to examine the relationship between TV and OS and local progression-free survival (LPFS). A cutoff value of tumor volume was identified to best discriminate patients with different 2-year OS rates, using receiver operating characteristic (ROC) analysis. RESULTS: A total of 157 patients were enrolled. The median tumor volume was 22.49 (2.52-90.13) ml. In the univariable analyses, tumor volume was significantly associated with OS (p < 0.001) and LPFS (p = 0.01). The relationships with OS (p = 0.009) and LPFS (p = 0.020) remained significant in multivariable analyses. Using ROC analysis, a TV of 26.69 ml was identified to predict the 2-year OS rate. To facilitate potential clinical use, 25 ml was designated as the final cutoff value. The 2-year OS and LPFS rates were 88.6 % vs 62.3 %, and 54.7 % vs 35.5 %, for patients with a TV ≤ 25 ml and > 25 ml, respectively. CONCLUSION: Tumor volume could predict the OS and LPFS of patients. We propose that tumor volume should be considered in the risk stratification and CIRT-based treatment for patients with LR-NPC.

Identification of novel molecular subtypes to improve the classification framework of nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) treatment is largely based on a 'one-drug-fits-all' strategy in patients with similar pathological characteristics. However, given its biological heterogeneity, patients at the same clinical stage or similar therapies exhibit significant clinical differences. Thus, novel molecular subgroups based on these characteristics may better therapeutic outcomes. METHODS: Herein, 192 treatment-naïve NPC samples with corresponding clinicopathological information were obtained from Fujian Cancer Hospital between January 2015 and January 2018. The gene expression profiles of the samples were obtained by RNA sequencing. Molecular subtypes were identified by consensus clustering. External NPC cohorts were used as the validation sets. RESULTS: Patients with NPC were classified into immune, metabolic, and proliferative molecular subtypes with distinct clinical features. Additionally, this classification was repeatable and predictable as validated by the external NPC cohorts. Metabolomics has shown that arachidonic acid metabolites were associated with NPC malignancy. We also identified several key genes in each subtype using a weighted correlation network analysis. Furthermore, a prognostic risk model based on these key genes was developed and was significantly associated with disease-free survival (hazard ratio, 1.11; 95% CI, 1.07-1.16; P < 0.0001), which was further validated by an external NPC cohort (hazard ratio, 7.71; 95% CI, 1.39-42.73; P < 0.0001). Moreover, the 1-, 3-, and 5-year areas under the curve were 0.84 (95% CI, 0.74-0.94), 0.81 (95% CI, 0.73-0.89), and 0.82 (95% CI, 0.73-0.90), respectively, demonstrating a high predictive value. CONCLUSIONS: Overall, we defined a novel classification of nasopharyngeal carcinoma (immune, metabolism, and proliferation subtypes). Among these subtypes, metabolism and proliferation subtypes were associated with advanced stage and poor prognosis of NPC patients, whereas the immune subtype was linked to early stage and favorable prognosis.

A protocol for a randomized trial evaluating the role of carbon-ion radiation therapy plus camrelizumab for patients with locoregionally recurrent nasopharyngeal carcinoma.

PURPOSE: Management of locoregionally recurrent nasopharyngeal carcinoma (LR NPC) is difficult. Although carbon-ion radiation therapy (CIRT) could substantially improve the overall survival (OS) of those patients, around 40% of the patients may still develop local failure. Further improvement of the disease control is necessary. Immunotherapy, such as immune checkpoint inhibitors (ICIs) becomes a promising antitumor treatment. The role of ICIs was proved in head and neck cancers including recurrent/metastatic NPC. Preclinical studies indicated potential synergistic effects between radiation therapy and ICIs. Therefore, we conduct a randomized phase 2 trial to evaluate the efficacy and safety of camrelizumab, an anti-PD-1 monoclonal antibody, along with CIRT in patients with LR NPC. METHODS: Patients will be randomly assigned at 1:1 to receive either standard CIRT with 63 Gy (relatively biological effectiveness, [RBE]) in 21 fractions, or standard CIRT plus concurrent camrelizumab. Camrelizumab will be administered intravenously with a dose of 200 mg, every 2 week, for a maximum of 1 year. We estimate addition of camrelizumab will improve the 2-year progression-free survival (PFS) from 45% to 60%. A total of 146 patients (with a 5% lost to follow-up rate) is required to yield a type I error of 0.2, and a power of 0.8. RESULTS AND CONCLUSION: The results of the trial may shed insights on the combined therapy with ICIs and CIRT.

Particle beam radiotherapy in the treatment of WHO grade 2 and 3 meningiomas: an early experience from Shanghai Proton and Heavy Ion Center.

PURPOSE: To investigate the efficacy and safety of particle beam radiotherapy (PBRT) in the management of patients with WHO grade 2 and 3 meningiomas. METHODS: Thirty-six consecutive and non-selected patients with WHO grade 2 (n = 28) and grade 3 (n = 8) meningiomas were treated at the Shanghai Proton and Heavy Ion Center, from May 2015 to March 2022. The median age of the cohort at PBRT was 48 years. There were 25 and 11 patients treated with PBRT in the setting of newly diagnosed diseases and progressive/recurrent diseases, respectively. PBRT was utilized as re-irradiation in 5 patients. Proton radiotherapy (PRT) and carbon-ion radiotherapy (CIRT), with a median dose of 60 Gy-Equivalent (GyE), were provided to 30 and 6 patients, respectively. RESULTS: With a median follow-up of 23.3 months, the local control rates were 92.0%, 82.0%, and 82.0% at 1, 2, and 3 years for the entire cohort, respectively. Patients with WHO grade 2 meningiomas (100%, 94.1%, 94,1% at 1,2,3 years) had a much better local control than those with WHO grade 3 meningiomas (50%, 25%, 25% at 1,2,3 years; P < 0.001). Three patients, all with WHO grade 3 meningiomas, had deceased at the time of this analysis. Multivariate analyses revealed that WHO grade (grade 2 vs. 3) (p = 0.016) was a significant prognosticator for local control. No severe toxicities (G3 or above) were observed. CONCLUSIONS: Treatment-induced efficacy and toxicities to PBRT in WHO grade 2 and 3 meningiomas were both highly acceptable. Longer follow-up is needed to evaluate the long-term outcome in terms of disease control, survival, as well as potential late effects.

Carbon ion radiotherapy combined with immunotherapy: synergistic anti-tumor efficacy and preliminary investigation of ferroptosis.

Carbon ion radiotherapy (CIRT) may yield satisfactory clinical outcomes for patients who are resistant to radiotherapy. However, the therapeutic impact of carbon ions is still limited in certain recurring or refractory tumors. Therefore, we aimed to evaluate the synergistic anti-tumor effects of immune checkpoint inhibitors (ICIs) in combination with CIRT. We then explored the involvement of ferroptosis in a preliminary investigation. A tumor-bearing mouse model was established, and mice were inoculated subcutaneously with B16-OVA cells into the flanks of both hind legs. Mice were assigned to four groups to receive CIRT, ICIs, or combined treatment. Thereafter, we conducted transcriptome sequencing (RNA-seq), bioinformatics analysis, and various immune-related experiments on the available tumor tissues to investigate differences in the synergistic anticancer effects and potential mechanisms across the groups. The combination therapies significantly improved the survival of mice and inhibited tumor growth, both at local and distant sites. Based on bioinformatics and RNA-seq data, immune-related pathways and genes, immune cell infiltration, and the production of cytokines and chemokines were the most enhanced in the combined treatment group compared to other groups. Finally, we identified a potential role for ferroptosis in the development of local anti-tumor synergy during CIRT combination treatment. In conclusion, this study showed that CIRT and ICIs can enhance the anti-tumor immune effects. We also proposed that ferroptosis may induce anti-tumor effects in CIRT combination therapy, offering a unique perspective on its ability to enhance immunotherapy responses.

Preliminary clinical outcomes of head and neck squamous cell carcinoma treated with particle beam radiation therapy.

PURPOSE: Further improvement in clinical outcomes is needed for patients with head and neck squamous cell carcinoma (HNSCC), as there is typically a poor prognosis at diagnosis. This study aimed to report the preliminary therapeutic outcomes and side effects in patients with HNSCC receiving particle beam radiotherapy (PBRT), owing to the physical and biological advantages of this approach. METHODS: We retrospectively analyzed 68 patients with newly diagnosed HNSCC who received PBRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between August 2015 and December 2020. The Kaplan-Meier approach was used to determine overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS). Common Terminology Criteria for Adverse Events (CTCAE) 4.03 was also used to grade acute and late toxicities. RESULTS: With a median follow-up time of 24.5 months (range, 3-65), the 3-year OS, DSS, PFS, LRFS, RRFS, and DMFS rates for the entire cohort were 79.0%, 84.7%, 67.9%, 83.5%, 83.3%, and 96.1%, respectively. Univariate and multivariate analyses showed that N category was a significant predictor of OS, PFS, and RRFS. In terms of acute toxicities, two patients demonstrated severe mucositis or dysphagia, and two patients also displayed a late toxicity of significant mucosal necrosis. CONCLUSION: These findings suggest that PBRT can provide patients with HNSCC with a promising therapeutic benefit and manageable toxicity. Prospective evaluation of clinical outcomes with PBRT for HNSCC is warranted, with an emphasis on clinical effectiveness as well as adverse effects and patient quality of life.

Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation.

The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

Proton radiotherapy in the treatment of IDH-mutant diffuse gliomas: an early experience from shanghai proton and heavy ion center.

PURPOSE: According to the presence or absence of isocitrate dehydrogenase (IDH) mutation, the 2021 WHO classification system bisected diffuse gliomas into IDH-mutant tumors and IDH-wildtype tumors. This study was aimed to evaluate the outcomes of proton radiotherapy treating IDH-mutant diffuse gliomas. PATIENTS AND METHODS: Between May 2015 and May 2022, a total of 52 consecutive patients with IDH-mutant diffuse gliomas were treated at Shanghai Proton and Heavy Ion Center. Tumor histologies were 33 cases of astrocytoma and 19 cases of oligodendroglioma. Tumor classified by WHO grade 2, 3 and 4 were 22, 25, and 5 cases, respectively. All 22 patients with WHO grade 2 tumors and one patient with brain stem WHO grade 4 tumor were irradiated with 54GyE. The other 29 patients with WHO grade 3 and 4 tumors were irradiated with 60GyE. Temozolomide was recommended to all patients, and was eventually conducted in 50 patients. RESULTS: The median follow-up time was 21.7 months. The 12/24-month progression-free survival (PFS) and overall survival (OS) rates for the entire cohort were 97.6%/78.4% and 100%/91.0% group. Examined by both univariate and multivariate analysis, WHO grade of tumor were of the most significant impact for both PFS and OS. No severe acute toxicity (grade 3 or above) was found. In terms of late toxicity, grade 3 radio-necrosis was developed in one case of oligodendroglioma, WHO grade 3. CONCLUSION: Proton radiotherapy produced a favorable outcome with acceptable adverse-effects in patients with IDH-mutant diffuse gliomas.

Identification of molecular subtypes based on inflammatory response in lower-grade glioma.

BACKGROUND: Inflammatory response is an important characteristic affecting prognosis and therapeutic response in lower-grade glioma (LGG). However, the molecular subtypes based on inflammatory response are still under exploitation. METHODS: The RNA sequencing, somatic mutation, and corresponding clinical data from 1205 LGG patients were obtained from the TCGA, CGGA, and Rembrandt cohorts. Consensus clustering was performed to identify molecular subtypes associated with inflammation. Prognosis, clinicopathologic features, immune cell infiltration, and somatic mutation profile were compared among these inflammation-associated subtypes. RESULTS: Our results demonstrate that LGG could be categorized into inflammation-, low, -mid, and -high subtypes with distinct clinicopathologic features, prognostic and tumor microenvironment. We established that this categorization was reproducible, as well as predictable. In general, inflammation-high subtype presents a dismal prognosis with the immunosuppressive microenvironment and high frequency of oncogene mutation. Inversely, inflammation-low subtype was associated with the most favorable clinical outcomes with the immunoreactive microenvironment among three subtypes. Moreover, we develop and validate an inflammation-related prognostic model, which shows strong power for prognosis assessment. CONCLUSION: In conclusion, we established a novel glioma classification based on the inflammation subtype. This classification had significant outcomes for estimating the prognosis, as well as the tumor microenvironment.

Mesenchymal Stem Cells Inhibits Migration and Vasculogenic Mimicry in Nasopharyngeal Carcinoma Via Exosomal MiR-125a.

Vasculogenic mimicry (VM) is a kind of tumor vasculature providing blood supply for tumor growth, and the formation of VM is independent of vascular endothelial cells. Instead, VM structures are formed by differentiated tumor cells such as nasopharyngeal carcinoma cells. Recently, studies have shown that anti-angiogenic therapy failed to improve the overall survival for patients, namely, nasopharyngeal carcinoma patients. The existence of VM structure is probably one of the reasons for resistance for anti-angiogenic therapy. Therefore, it is important to study the mechanism for VM formation in nasopharyngeal carcinoma. In this study, the bioinformatic analysis revealed that microRNA-125a-3p (miR-125a) was highly expressed in normal nasopharyngeal epithelial tissue than in nasopharyngeal carcinoma. An in vitro study demonstrated that miR-125a plays an inhibitory role in nasopharyngeal carcinoma cell migration and VM formation, and further studies confirmed that TAZ is a direct downstream target for miR-125a. On this basis, we artificially engineered human mesenchymal stem cells (MSCs) to generate exosomes with high miR-125a expression. Treatment with these miR-125a-over-expressing exosomes attenuated the migration and VM formation in nasopharyngeal carcinoma cells. In addition, the inhibitory role of these exosomes on VM formation and migration in nasopharyngeal carcinoma was also confirmed in vivo. Overall, the current study shows that MSCs can be utilized to generate exosomes with high miR-125a level, which could be therapeutic nanoparticles targeting VM formation in nasopharyngeal carcinoma and used as a complement to anti-angiogenic therapy in the future.

Multi-Omics Data Analyses Identify B7-H3 as a Novel Prognostic Biomarker and Predict Response to Immune Checkpoint Blockade in Head and Neck Squamous Cell Carcinoma.

B7 homolog 3 (B7-H3) is a recently found superfamily B7 molecule and therefore has significant involvement in immunological regulation. However, the relationships of B7-H3 expression with the tumor microenvironment (TME), response to immunotherapy, and prognosis in head and neck squamous cell carcinoma (HNSCC) are still unknown. In the present analysis, we determined B7-H3 as a novel biomarker that predicts the prognosis and response to immunotherapy in HNSCC. B7-H3 expression is enhanced in HNSCC compared to normal sample and is stably expressed in HNSCC cell line. Besides, high B7-H3 expression is correlated with a dismal prognosis and resistance to immunotherapy and contributes to an immunosuppressive microenvironment. Moreover, single-cell RNA sequencing (scRNA-seq) analysis shows that B7-H3 is mainly expressed in the stromal as well as malignant cells. In conclusion, the study provides insight in understanding the prognostic value of B7-H3 in HNSCC and highlights its involvement in promoting the immunosuppressive microenvironment, which presents an attractive strategy for antibody-based immunotherapy.

Vasculogenic mimicry formation in EBV-associated epithelial malignancies.

Epstein-Barr virus (EBV)-associated epithelial cancers, including nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancers, termed EBVaGC, represent 80% of all EBV-related malignancies. However, the exact role of EBV in epithelial cancers remains elusive. Here, we report that EBV functions in vasculogenic mimicry (VM). Epithelial cancer cells infected with EBV develop tumor vascular networks that correlate with tumor growth, which is different from endothelial-derived angiogenic vessels and is VEGF-independent. Mechanistically, activation of the PI3K/AKT/mTOR/HIF-1α signaling cascade, which is partly mediated by LMP2A, is responsible for EBV-induced VM formation. Both xenografts and clinical samples of NPC and EBVaGC exhibit VM histologically, which are correlated with AKT and HIF-1α activation. Furthermore, although anti-VEGF monotherapy shows limited effects, potent synergistic antitumor activities are achieved by combination therapy with VEGF and HIF-1α-targeted agents. Our findings suggest that EBV creates plasticity in epithelial cells to express endothelial phenotype and provides a novel EBV-targeted antitumor strategy.

Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation.

Epstein-Barr virus (EBV) is a human cancer-related virus closely associated with lymphoid and epithelial malignancies, and EBV glycoprotein B (gB) plays an essential role in viral entry into both B cells and epithelial cells by promoting cell-cell fusion. EBV gB is exclusively modified with high-mannose-linked N-glycans and primarily localizes to the endoplasmic reticulum (ER) with low levels on the plasma membrane (PM). However, the mechanism through which gB is regulated within host cells is largely unknown. Here, we report the identification of F-box only protein 2 (FBXO2), an SCF ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans and attenuates EBV infectivity by targeting N-glycosylated gB for degradation. gB possesses seven N-glycosylation sites, and FBXO2 directly binds to these high-mannose moieties through its sugar-binding domain. The interaction promotes the degradation of glycosylated gB via the ubiquitin-proteasome pathway. Depletion of FBXO2 not only stabilizes gB but also promotes its transport from the ER to the PM, resulting in enhanced membrane fusion and viral entry. FBXO2 is expressed in epithelial cells but not B cells, and EBV infection up-regulates FBXO2 levels. In summary, our findings highlight the significance of high-mannose modification of gB and reveal a novel host defense mechanism involving glycoprotein homeostasis regulation.

OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma.

Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.

Immunization With Fc-Based Recombinant Epstein-Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model.

Epstein-Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications.

TNFRSF19 Inhibits TGFß Signaling through Interaction with TGFß Receptor Type I to Promote Tumorigenesis.

Genetic susceptibility underlies the pathogenesis of cancer. We and others have previously identified a novel susceptibility gene TNFRSF19, which encodes an orphan member of the TNF receptor superfamily known to be associated with nasopharyngeal carcinoma (NPC) and lung cancer risk. Here, we show that TNFRSF19 is highly expressed in NPC and is required for cell proliferation and NPC development. However, unlike most of the TNF receptors, TNFRSF19 was not involved in NFκB activation or associated with TRAF proteins. We identified TGFß receptor type I (TßRI) as a specific binding partner for TNFRSF19. TNFRSF19 bound the kinase domain of TßRI in the cytoplasm, thereby blocking Smad2/3 association with TßRI and subsequent signal transduction. Ectopic expression of TNFRSF19 in normal epithelial cells conferred resistance to the cell-cycle block induced by TGFß, whereas knockout of TNFRSF19 in NPC cells unleashed a potent TGFß response characterized by upregulation of Smad2/3 phosphorylation and TGFß target gene transcription. Furthermore, elevated TNFRSF19 expression correlated with reduced TGFß activity and poor prognosis in patients with NPC. Our data reveal that gain of function of TNFRSF19 in NPC represents a mechanism by which tumor cells evade the growth-inhibitory action of TGFß.Significance:TNFRSF19, a susceptibility gene for nasopharyngeal carcinoma and other cancers, functions as a potent inhibitor of the TGFß signaling pathway.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3469/F1.large.jpg Cancer Res; 78(13); 3469-83. ©2018 AACR.

Beneficial effects of anti-EGFR agents, Cetuximab or Nimotuzumab, in combination with concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma.

OBJECTIVE: This study aimed to evaluate the efficacy and safety in locoregionally advanced nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) plus Cetuximab (CTX) or Nimotuzumab (NTZ) compared to those receiving induction chemotherapy (IC) plus CCRT. MATERIALS AND METHODS: From January 2008 to December 2013, 715 eligible patients were enrolled in the study. Using propensity scores to adjust for gender, age, Karnofsky performance status (KPS), tumor stage, node stage, and clinical stage, a well-balanced cohort was created by matching each patient who received CTX/NTZ plus CCRT (137 patients) with two patients who underwent IC plus CCRT (274 patients). The primary endpoint was overall survival (OS), and other outcome variables included disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional relapse-free survival (LRRFS). RESULTS AND CONCLUSION: The median follow-up was 57.0 months and 55.0 months for the CTX/NTZ plus CCRT group and IC plus CCRT group, respectively. No significant differences were found between the CTX/NTZ plus CCRT group and the IC plus CCRT group in 3-year OS (95.5% vs. 94.7%, P = 0.083), 3-year DFS (93.3% vs. 86.1%, P = 0.104), 3-year DMFS (96.2% vs. 92.5%, P = 0.243) and 3-year LRRFS (97.0% vs. 95.1%, P = 0.297). Patients undergoing IC plus CCRT suffered from severe hematologic toxicity and diarrhea compared with those treated with CTX/NTZ plus CCRT. The combination of CTX/NTZ with CCRT is comparable to IC plus CCRT treatment in survival outcomes for locoregionally advanced NPC patients but has a better safety profile than IC plus CCRT treatment.