Response In Nasopharyngeal Carcinoma Research Articles

Targeting RPA promotes autophagic flux and the antitumor response to radiation in nasopharyngeal carcinoma

BackgroundAutophagy is involved in nasopharyngeal carcinoma (NPC) radioresistance. Replication protein A 1 (RPA1) and RPA3, substrates of the RPA complex, are potential therapeutic targets for reversing NPC radioresistance. Nevertheless, the role of RPA in autophagy is not adequately understood. This investigation was performed to reveal the cytotoxic mechanism of a pharmacologic RPA inhibitor (RPAi) in NPC cells and the underlying mechanism by which RPAi-mediated autophagy regulates NPC radiosensitivity.Methods and resultsWe characterized a potent RPAi (HAMNO) that was substantially correlated with radiosensitivity enhancement and proliferative inhibition of in vivo and in NPC cell lines in vitro. We show that the RPAi induced autophagy at multiple levels by inducing autophagic flux, AMPK/mTOR pathway activation, and autophagy-related gene transcription by decreasing glycolytic function. We hypothesized that RPA inhibition impaired glycolysis and increased NPC dependence on autophagy. We further demonstrated that combining autophagy inhibition with chloroquine (CQ) treatment or genetic inhibition of the autophagy regulator ATG5 and RPAi treatment was more effective than either approach alone in enhancing the antitumor response of NPC to radiation.ConclusionsOur study suggests that HAMNO is a potent RPAi that enhances radiosensitivity and induces autophagy in NPC cell lines by decreasing glycolytic function and activating autophagy-related genes. We suggest a novel treatment strategy in which pharmacological inhibitors that simultaneously disrupt RPA and autophagic processes improve NPC responsiveness to radiation.

Multiple TMA-aided CRISPR/Cas13a platform for highly sensitive detection of IL-15 to predict immunotherapeutic response in nasopharyngeal carcinoma

BackgroundImmune checkpoint inhibitors (ICIs)-based treatments have been recommended as the first line for refractory recurrent and/or metastatic nasopharyngeal carcinoma (NPC) patients, yet responses vary, and predictive biomarkers are urgently needed....

Can the apparent transverse relaxation rate (R2*) evaluate the efficacy of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma? a preliminary experience

BackgroundThe use of the apparent transverse relaxation rate (R2*) in nasopharyngeal carcinoma (NPC) has not been previously reported in the literature. The aim of this study was to investigate the role of the R2* value in evaluating response to concurrent chemoradiotherapy (CCRT) in patients with NPC.MethodsForty-one patients with locoregionally advanced NPC confirmed by pathology were examined by blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) before and after CCRT, and conventional MRI was performed 3 months after the completion of CCRT. All patients were divided into a responding group (RG) and a nonresponding group (NRG), according to MRI findings 3 months after the end of treatment. The R2* values before (R2*preT) and after (R2*postT) CCRT and the ΔR2* (ΔR2*=R2*postT – R2*preT) were calculated in the tumor.ResultsAmong the 41 patients, 26 were in the RG and 15 were in the NRG. There was no statistical difference in the R2*preT between RG and NRG (P = 0.307); however, there were significant differences in R2*postT and ΔR2* (P < 0.001). The area under the curve of R2*postT and ΔR2* for predicting the therapeutic response of NPC was 0.897 and 0.954, respectively, with cutoff values of 40.95 and 5.50 Hz, respectively.ConclusionThe R2* value can be used as a potential imaging indicator to evaluate the therapeutic response of locoregionally advanced NPC.

A two-stage genome-wide association study identifies novel germline genetic variations in CACNA2D3 associated with radiotherapy response in nasopharyngeal carcinoma

BackgroundRadiotherapy (RT) is the standard treatment for nasopharyngeal carcinoma (NPC). However, due to individual differences in radiosensitivity, biomarkers are needed to tailored radiotherapy to cancer patients. However, comprehensive genome-wide radiogenomic studies on them are still lacking. The aim of this study was to identify genetic variants associated with radiotherapy response in patients with NPC.MethodsThis was a large‑scale genome-wide association analysis (GWAS) including a total of 981 patients. 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant loci were further genotyped using MassARRAY system and TaqMan SNP assays in the validation stages of 847 patients. This study used logistic regression analysis and multiple bioinformatics tools such as PLINK, LocusZoom, LDBlockShow, GTEx, Pancan-meQTL and FUMA to examine genetic variants associated with radiotherapy efficacy in NPC.ResultsAfter genome-wide level analysis, 19 SNPs entered the validation stage (P < 1 × 10− 6), and rs11130424 ultimately showed statistical significance among these SNPs. The efficacy was better in minor allele carriers of rs11130424 than in major allele carriers. Further stratified analysis showed that the association existed in patients in the EBV-positive, smoking, and late-stage (III and IV) subgroups and in patients who underwent both concurrent chemoradiotherapy and induction/adjuvant chemotherapy.ConclusionOur study showed that rs11130424 in the CACNA2D3 gene was associated with sensitivity to radiotherapy in NPC patients.Trial registration number: Effect of genetic polymorphism on nasopharyngeal carcinoma chemoradiotherapy reaction, ChiCTR-OPC-14005257, Registered 18 September 2014, http://www.chictr.org.cn/showproj.aspx?proj=9546.

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1-associating protein)-mediated TEAD4 m6A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC.

Prediction of short-term treatment outcome of nasopharyngeal carcinoma based on voxel incoherent motion imaging and arterial spin labeling quantitative parameters

PurposeTo evaluate the early response of chemoradiotherapy (CRT) in nasopharyngeal carcinoma (NPC) based on intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and three-dimensional pseudo-continuous arterial spin labeling (3D pCASL). Materials and methodsForty patients diagnosed with NPC were recruited and divided into complete remission (CR) and partial remission (PR) group after CRT. All patients underwent IVIM and ASL and the related parameters was obtained. These parameters include pure diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f), average blood flow ( BFavg), minimum blood flow (BFmin), and maximum blood flow (BFmax). Student’s t test was used to compare the difference in ASL and IVIM derived parameters between CR and PR. The Areas under curve (AUC) of the receiver operating characteristic (ROC) was used to analyze the diagnostic performance of each parameter of ASL and IVIM to the treatment outcome. Resultsthe D value of IVIM in CR group was lower than that of the PR group ( P = 0.014),. Among the parameters of ASL, the BFavg and BFmax of the CR group were higher than those of the PR group(p = 0.004,0.013), but the BFmin had no statistical significance in the two groups（P = 0.54）. AUC of D, BFavg, and BFmax is about 0.731, 0.753, and 0.724, respectively, all of their combined AUC diagnosis was 0.812. ConclusionThe early response of NPC after CRT can predict by IVIM’s diffusion parameters and ASL-related blood flow parameters.

STRESS granule-associated RNA-binding protein CAPRIN1 drives cancer progression and regulates treatment response in nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is a common malignancy of the head and neck that is mainly diagnosed in southern China and Southeast Asia, with a strong etiological link to Epstein‒Barr virus infection. Those with advanced-stage disease have a significantly worse prognosis. There is an urgent need to identify novel therapeutic targets for the recurrent or metastatic nasopharyngeal carcinoma. With a particular focus on Cell Cycle Associated Protein 1 (CAPRIN1), one of the important RNA-binding proteints associated with stress granule formation, we used RT‒qPCR and immunohistochemistry to validate CAPRIN1 expression in NPC tissues and cell lines. Further, CAPRIN1 expression was knocked down using siRNA, and the effect on cell proliferation and migration was systematically assessed by in vitro assays. As a result, we demonstrated that CAPRIN1 was elevated in NPC compared to adjacent normal tissues. Knockdown of CAPRIN1 in NPC cells inhibited proliferation and migration, involving the regulation of cell cycle protein CCND2 and EMT signaling, respectively. Notably, we found that CAPRIN1 knockdown promoted cell apoptosis by regulation of the expression of apoptosis-related proteins cleaved-PARP and cleaved-Caspase3. Knockdown of CAPRIN1 increased NPC cell sensitivity to rapamycin, and increased NPC cell sensitivity to cisplatin and to X-rays. In conclusion, CAPRIN1 might drive NPC proliferation, regulate cell cycle and apoptosis, and affect tumor cell response to anti-cancer agents and X-ray irradiation. CAPRIN1 might serve as a potential target for NPC.

Tumor Cell-Intrinsic E3 Ligase TRIM21 Restrains Radiation-Induced Antitumor Immunity by Decreasing Mitochondrial DNA Release from VDAC2 Oligomers

<h3>Purpose/Objective(s)</h3> Radiotherapy has been proved to activate antitumor immunity but how aberrantly expressed genes in cancer regulated this process remains elusive. <h3>Materials/Methods</h3> We identified TRIM21, an E3 ligase gene, by bioinformatics analysis based on gross sequencing and single-cell sequencing data of nasopharyngeal carcinoma (NPC). The impact of TRIM21on radiation-induced antitumor immune response was identified in vitro and in vivo by TRIM21 knockout. We also determined the prognosis value of TRIM21 in NPC tissues with immunohistochemical analysis. <h3>Results</h3> Tumor cell-intrinsic E3 ligase tripartite motif-containing 21(TRIM21) is inversely associated with CD8+ T cell antitumor immunity and radiation response in NPC. Knockout of TRIM21 promoted radiation-induced antigen presentation, chemokine expression, dendritic cells, and CD8+ T cells activation in vitro, and led to enhanced radiation efficacy and immune response in MC38 murine colon adenocarcinoma, and transplanted NPC tumor in humanized mice in vivo. In mechanism, knockout of TRIM21 reversed its degradation of mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2), which resulted in sufficient VDAC2 oligomerization, mitochondrial DNA release, and thus strengthened activation of STING and type I interferon signaling during radiation. Clinically, high expression of TRIM21 in NPC indicated poor prognosis and tumor relapse after radiation. <h3>Conclusion</h3> Tumor cell-intrinsic TRIM21 suppressed radiation-induced antitumor immunity and predicted poor survival in NPC patients.

Prediction of Response to Induction Chemotherapy Plus Concurrent Chemoradiotherapy for Nasopharyngeal Carcinoma Based on MRI Radiomics and Delta Radiomics: A Two-Center Retrospective Study.

ObjectiveWe aimed to establish an MRI radiomics model and a Delta radiomics model to predict tumor retraction after induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) for primary nasopharyngeal carcinoma (NPC) in non-endemic areas and to validate its efficacy.MethodsA total of 272 patients (155 in the training set, 66 in the internal validation set, and 51 in the external validation set) with biopsy pathologically confirmed primary NPC who were screened for pretreatment MRI were retrospectively collected. The NPC tumor was delineated as a region of interest in the two sequenced images of MRI before treatment and after IC, followed by radiomics feature extraction. With the use of maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms, logistic regression was performed to establish pretreatment MRI radiomics and pre- and post-IC Delta radiomics models. The optimal Youden’s index was taken; the receiver operating characteristic (ROC) curve, calibration curve, and decision curve were drawn to evaluate the predictive efficacy of different models.ResultsSeven optimal feature subsets were selected from the pretreatment MRI radiomics model, and twelve optimal subsets were selected from the Delta radiomics model. The area under the ROC curve, accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the MRI radiomics model were 0.865, 0.827, 0.837, 0.813, 0.776, and 0.865, respectively; the corresponding indicators of the Delta radiomics model were 0.941, 0.883, 0.793, 0.968, 0.833, and 0.958, respectively.ConclusionThe pretreatment MRI radiomics model and pre- and post-IC Delta radiomics models could predict the IC-CCRT response of NPC in non-epidemic areas.

Baseline Amide Proton Transfer Imaging at 3T Fails to Predict Early Response to Induction Chemotherapy in Nasopharyngeal Carcinoma.

BackgroundEarly identification of nasopharyngeal carcinoma (NPC) patients with high risk of failure to induction chemotherapy (IC) would facilitate prompt individualized treatment decisions and thus reduce toxicity and improve overall survival rate. This study aims to investigate the value of amide proton transfer (APT) imaging in predicting short-term response of NPC to IC and its potential correlation with well-established prognosis-related clinical characteristics.Methods and MaterialsA total of 80 pathologically confirmed NPC patients receiving pre-treatment APT imaging at 3T were retrospectively enrolled. Using asymmetry analysis, APT maps were calculated with mean (APTmean), 90th percentile (APT90) of APT signals in manually segmented NPC measured. APT values were compared among groups with different histopathological subtypes, clinical stages (namely, T, M, N, and overall stages), EBV-related indices (EBV-DNA), or responses to induction chemotherapy, using Mann–Whitney U test or Kruskal–Wallis H test.ResultsNPC showed significantly higher APTmean than normal nasopharyngeal tissues (1.81 ± 0.62% vs.1.32 ± 0.56%, P <0.001). APT signals showed no significant difference between undifferentiated and differentiated NPC subtypes groups, different EBV-DNA groups, or among T, N, M stages and overall clinical stages of II, III, IVA and IVB (all P >0.05). Similarly, baseline APT-related parameters did not differ significantly among different treatment response groups after IC, no matter if evaluated with RECIST criteria or sum volumetric regression ratio (SVRR) (all P >0.05).ConclusionNPC showed significantly stronger APT effect than normal nasopharyngeal tissue, facilitating NPC lesion detection and early identification. However, stationary baseline APT values exhibited no significant correlation with histologic subtypes, clinical stages and EBV-related indices, and showed limited value to predict short-term treatment response to IC.

Relationship between CD-8 Expression to Treatment Response in Nasopharyngeal Carcinoma Patient After Neoadjuvant Chemotherapy in Dr. Mohammad Hoesin Hospital Palembang

Background. Nasopharyngeal carcinoma (NPC) is the most common malignancy in head and neck in Indonesia with 19,943 new cases in 2020 resulting 13,399 deaths. Lymphocytes are cells that play a role in the anti-cancer immune response, especially CD-8 T-cells. Neoadjuvant chemotherapy is chemotherapy given before radiotherapy that aims to kill primary tumors and micrometastasis tumors. This study aims to find out the relationship of CD-8 expression to treatment response in NPC undergoing neoadjuvant chemotherapy at Dr. Mohammad Hoesin Hospital Palembang.&#x0D; Methods. This study is an analytical observational research study on a retrospective cohort basis. Data collection from medical records using total sampling in 15 patients pilot study of NPC patients undergoing neoadjuvant chemotherapy and conducted CD-8 examination at ORLHNS polyclinic Dr. Mohammad Hoesin Hospital Palembang from December 2018 to December 2019 that met the criteria of inclusion and exclusion.&#x0D; Results. From 15 samples, the average CD-8 test result before neoadjuvant chemotherapy was 24.54 ng/μL and after neoadjuvant chemotherapy was 193.56 ng/μL. There was a tendency to increase the average CD-8 from before to after completion of neoadjuvan chemotherapy with a statistically significant difference of p =0.001. ROC analysis found CD-8 cut off points is 23.76 ng/μL with an area below the curve is 0.667. There were no significant relationships between CD-8 to performance status and treatment response with p values of 0.289 and 0.219, respectively. &#x0D; Conclusions. There was a significant change between CD-8 before neoadjuvant chemotherapy and after neoadjuvant chemotherapy with increased CD-8 tendencies and trends from before to after 6 series neoadjuvant chemotherapy with CD-8 cut off points is 23.76 ng/μL. In this study there has not been a significant relationships between CD-8 to performance status and treatment response in NPC patients undergoing neoadjuvant chemotherapy.

Association between Foxp3 Tumor Infiltrating Lymphocyte Expression and Response After Chemoradiation in Nasopharyngeal Carcinoma

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a carcinoma originating from the surface epithelium of the nasopharynx with the highest incidence in China and South East Asia. Currently, many researchers are developing tumor microenvironment which can be assessed by tumor-infiltrating lymphochyte, and its association with treatment response in several tumors, including NPC. Foxp3, known as a regulatory T cell (Treg) marker, plays a role in the immunoregulatory environment of tumor cells and can be used as a prognostic factor. The relationship between Foxp3 expression and treatment response is considered as one of the factors affecting the prognosis of NPC. AIM: This study aims to determine the relationship between Foxp3 expression and treatment response in NPC. MATERIALS AND METHODS: A cross-sectional study was done to analyze the association between Foxp3 and treatment response in NPC. This study included 60 samples who were diagnosed with non-keratinizing NPC at the Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Cipto Mangunkusumo Hospital from January 2018 until December 2020. Immunohistochemistry was done to evaluate the expression of Foxp3. Foxp3 expression was evaluated in the intratumoral and peritumoral areas. RESULTS: Among 60 patients, the number of males were more than females (66.7%, 33.3%, respectively) with a ratio of 2:1. There was statistically significant difference between intratumoral and total Foxp3 expression and treatment response (p &lt; 0.05, p = 0.001, respectively); however, no significant differences found between peritumoral Foxp3 expression and treatment response (p = 0.114). CONCLUSION: Foxp3 expression had a statistically significant relationship with response therapy after chemoradiation.

Comparison of the pre-treatment functional MRI metrics\u2019 efficacy in predicting Locoregionally advanced nasopharyngeal carcinoma response to induction chemotherapy

BackgroundFunctional MRI (fMRI) parameters analysis has been proven to be a promising tool of predicting therapeutic response to induction chemotherapy (IC) in nasopharyngeal carcinoma (NPC). The study was designed to identify and compare the value of fMRI parameters in predicting early response to IC in patients with NPC.MethodsThis prospective study enrolled fifty-six consecutively NPC patients treated with IC from January 2021 to May 2021. Conventional diffusion weighted imaging (DWI), diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) protocols were performed before and after IC. Parameters maps (ADC, MD, MK, Dslow, Dfast, PF, Ktrans, Ve and Kep) of the primary tumor were calculated by the Functool post-processing software. The participants were classified as responding group (RG) and non-responding group (NRG) according to Response Evaluation Criteria in Solid Tumors 1.1. The fMRI parameters were compared before and after IC and between RG with NRG. Logistic regression analysis and ROC were performed to further identify and compare the efficacy of the parameters.ResultsAfter IC, the mean values of ADC(p < 0.001), MD(p < 0.001), Dslow(p = 0.001), PF(p = 0.030) and Ve(p = 0.003) significantly increased, while MK(p < 0.001), Dfast(p = 0.009) and Kep(p = 0.003) values decreased dramatically, while no significant difference was detected in Ktrans(p = 0.130). Compared with NRG, ADC-pre(p < 0.001), MD-pre(p < 0.001) and Dslow-pre(p = 0.002) values in RG were lower, while MK-pre(p = 0.017) values were higher. The areas under the ROC curves for the ADC-pre, MD-pre, MK-pre, Dslow-pre and PRE were 0.885, 0.855, 0.809, 0.742 and 0.912, with the optimal cutoff value of 1210 × 10− 6 mm2/s, 1010 × 10− 6 mm2/s, 832 × 10− 6, 835 × 10− 6 mm2/s and 0.799 respectively.ConclusionsThe pretreatment conventional DWI (ADC), DKI (MD and MK), and IVIM (Dslow) values derived from fMRI showed a promising potential in predicting the response of the primary tumor to IC in NPC patients.Trial registrationThis study was approved by ethics board of the Chinese PLA General Hospital, and registered on January 30, 2021, in Chinese Clinical Trial Registry (ChiCTR2100042863).

Exploration of a Novel Prognostic Risk Signature and Its Effect on the Immune Response in Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic carcinoma with different molecular characteristics and clinical outcomes. In this work, we aimed to establish a novel gene signature that could predict the prognosis of NPC patients. A total of 13 significant genes between the recurrence/metastasis (RM) group and the no recurrence/metastasis (no-RM) group were identified by machine learning from RNA-Seq data including 60 NPC tumor biopsies. Based on these genes, a 4-mRNA signature (considering U2AF1L5, TMEM265, GLB1L and MLF1) was identified. Receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses indicated that this signature had good prognostic value for NPC. The overall survival (OS) and progression-free survival (PFS) of the patients in the high-risk group were significantly shorter than those of the patients in the low-risk group (p = 0.00126 and p = 0.000059, respectively). The area under the ROC curve (AUC) values of the 4-mRNA signature were higher than those of T stage and N stage for OS (0.893 vs 0.619 and 0.582, respectively) and PFS (0.86 vs 0.538 and 0.622, respectively). Furthermore, the 4-mRNA signature was closely associated with cell proliferation and the immune response. The expression of GLB1L and TMEM265 was associated with the level of tumor-infiltrating immune cells (r > 0.4, p < 0.05). We have validated the model through measuring the expression levels of the 4-mRNA signature by qRT-PCR, in an independent cohort of NPC patients. Here, we report a novel gene signature that can serve as a new tool for predicting the prognosis of NPC patients.

Diffusion-weighted MRI for predicting treatment response in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis

Early prediction of treatment response in nasopharyngeal carcinoma is clinically relevant for optimizing treatment strategies. This meta-analysis was performed to evaluate whether apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) can predict treatment response of patients with nasopharyngeal carcinoma. A systematic search of PubMed-MEDLINE and Embase was performed to identify relevant original articles until July 22, 2021. We included studies which performed DWI for predicting locoregional treatment response in nasopharyngeal carcinoma treated with neoadjuvant chemotherapy, definitive chemoradiation, or radiation therapy. Hazard ratios were meta-analytically pooled using a random-effects model for the pooled estimates of overall survival, local relapse-free survival, distant metastasis-free survival and their 95% CIs. ADC showed a pooled sensitivity of 87% (95% CI 72–94%) and specificity of 70% (95% CI 56–80%) for predicting treatment response. Significant between-study heterogeneity was observed for both pooled sensitivity (I2 = 68.5%) and specificity (I2 = 92.2%) (P < 0.01). The pooled hazard ratios of low pretreatment ADC for assessing overall survival, local relapse-free survival, and distant metastasis-free survival were 1.42 (95% CI 1.09–1.85), 2.31 (95% CI 1.42–3.74), and 1.35 (95% CI 1.05–1.74), respectively. In patients with nasopharyngeal carcinoma, pretreatment ADC demonstrated good predictive performance for treatment response.

MRI-based radiomics as response predictor to radiochemotherapy for metastatic cervical lymph node in nasopharyngeal carcinoma.

To establish and substantiate MRI-based radiomic models to predict the treatment response of metastatic cervical lymph node to radiochemotherapy in patients with nasopharyngeal carcinoma (NPC). A total of 145 consecutive patients with NPC were enrolled including 102 in primary cohort and 43 in validation cohort. Metastatic lymph nodes were diagnosed according to radiologic criteria and treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors. A total of 2704 radiomic features were extracted from contrast-enhanced T1 weighted imaging (CE- T1WI) and T2 weighted imaging (T2WI) for each patient, and were selected to construct radiomic signatures for CE-T1WI, T2WI, and combined CE-T1WI and T2WI, respectively. The area under curve (AUC) of receiver operating characteristic, sensitivity, specificity, and accuracy were used to estimate the performance of these radiomic models in predicting treatment response of metastatic lymph node. No significant difference of AUC was found among radiomic signatures of CE-T1WI, T2WI, and combined CE-T1WI and T2WI in the primary and validation cohorts (all p > 0.05). For combined CE-T1WI and T2WI data set, 12 features were selected to develop the radiomic signature. The AUC, sensitivity, specificity, and accuracy were 0.927 (0.878-0.975), 0.911 (0.804-0.970), 0.826 (0.686-0.922), and 0.872 (0.792-0.930) in primary cohort, and were 0.772 (0.624-0.920), 0.792 (0.578-0.929), 0.790 (0.544-0.939), and 0.791 (0.640-0.900) in validation cohort. MRI-based radiomic models were developed to predict the treatment response of metastatic cervical lymph nodes to radiochemotherapy in patients with NPC, which might facilitate individualized therapy for metastatic lymph nodes before treatment. Predicting the response in patients with NPC before treatment may allow more individualizing therapeutic strategy and avoid unnecessary side-effects and costs. Radiomic features extracted from metastatic cervical lymph nodes showed promising application for predicting the treatment response in NPC.

M6A Reader YTHDC2 Promotes Radiotherapy Resistance of Nasopharyngeal Carcinoma via Activating IGF1R/AKT/S6 Signaling Axis.

N6-methyladenosine (m6A) modification has been reported as a critical regulator of gene transcript expression. Although m6A modification plays important roles in tumor development, its role in therapeutic resistance remains unknown. In this study, we aimed to examine the expression level of m6A-modification related proteins and elucidate the effect of m6A-related proteins on radiation response in nasopharyngeal carcinoma (NPC). Among the genes that participated in m6A modification, YTHDC2, a m6A reader, was found to be consistently highly expressed in radioresistant NPC cells. Knocking down of YTHDC2 expression in radioresistant NPC cells improved the therapeutic effect of radiotherapy in vitro and in vivo, whereas overexpression of YTHDC2 in radiosensitive NPC cells exerted an opposite effect. Bioinformatics and mechanistic studies revealed that YTHDC2 could physically bound to insulin-like growth factor 1 receptor (IGF1R) messenger RNA and promoted translation initiation of IGF1R mRNA, which in turn activated the IGF1R-AKT/S6 signaling pathway. Thus, the present study suggests that YTHDC2 promotes radiotherapy resistance of NPC cells by activating the IGF1R/ATK/S6 signaling axis and may serve as a potential therapeutic target in radiosensitization of NPC cells.

Abstract B28: ERAP2 overexpression is a marker for reduced anti-PD-1 response in nasopharyngeal carcinoma

Abstract Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial cancer common in the Southern Chinese population. Patients with recurrent or metastatic NPC treated with PD-1 blockade showed a response rate of 20.5%, with no correlation observed between the expression of PD-L1 and treatment response. In an effort to identify biomarkers for anti-PD-1 treatment response, we evaluated a cohort of 10 NPC patients with recurrent or metastatic NPC treated with nivolumab or pembrolizumab. Laser capture microdissection was performed on pretreatment biopsies, with tumor and microenvironment compartments separately microdissected. Nasopharyngeal epithelium from normal nasopharyngeal biopsies were also microdissected as controls. Smart-3SEQ, a novel 3´ end RNA-Seq technique that allows for the accurate quantification of transcript abundance in FFPE samples, was performed to obtain gene expression libraries. ERAP2, a zinc metalloaminopeptidase that performs N-terminal trimming of antigenic epitopes for presentation by MHC class I, was among the most highly upregulated genes in the tumor compartment of nonresponders (adjusted p = 0.033). ERAP2 overexpression was also observed in NPC tumors compared to normal controls. Immunohistochemistry validated the overexpression of ERAP2 in nonresponders, while responders had similar expression to normal controls. In conclusion, ERAP2 is overexpressed in NPC tumors and is a promising biomarker for reduced anti-PD-1 response in NPC. Citation Format: Joshua K. Tay, Brigette B.Y. Ma, Sushama Varma, Yaw Chyn Lim, Chee Seng Tan, Kwok Wai Lo, John B. Sunwoo, Kevin J. Cullen, Boon Cher Goh, Robert B. West. ERAP2 overexpression is a marker for reduced anti-PD-1 response in nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B28.

The Homologous Recombination Repair Pathway is Associated with Resistance to Radiotherapy in Nasopharyngeal Carcinoma.

Radiotherapy plays a major role in the management of nasopharyngeal carcinoma (NPC). However, the radioresistant cells limit its efficiency and drive recurrence inside the irradiated tumor volume leading to poor outcome for patients. To illuminate the signal pathway involved in the radioresistance and evaluate the potential for predicting NPC response to radiotherapy, we established the radioresistant NPC cell line (CNE2-RR) derived from NPC cell line CNE2 by gradually increased the radiation dose (total 60 Gy), and the radioresistance of CNE2-RR cells was evaluated by the colony formation, FCM and comet assays. Furthermore, comparison of established CNE2-RR cell line to parental cell line found the homologous recombination repair (HRR) proteins differences involved in NPC radioresistance. In addition, the differentially expressed proteins were further validated by western blotting, immunofluorescence and IHC in tumor xenografs and radioresistant NPC tissues. Furthermore, the correlation of HRR proteins expression levels with NPC radioresistance were evaluated. The results showed that the upregulation of HRR proteins were significantly correlated with NPC radioresistance. In addition, using the Youden Index cutoff value, a panel of the HRR proteins analyses revealed a sensitivity of 70%, specificity of 72%. Furthermore, silencing NFBD1 enhanced the radiosensitivity of CNE2-RR cells by impairing IR-inducing γ-H2AX and HR proteins foci formation. These results suggest that controlling the HRR signaling pathway may hold promise to overcome NPC radioresistance.

Clinical significance of the post-radiotherapy 18F-fludeoxyglucose positron emission tomography response in nasopharyngeal carcinoma

Objective:The aim of the present study was to evaluate the clinical significance of the post-radiotherapy 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) response for detecting residual disease and predicting survival outcome in patients with nasopharyngeal cancer.Methods:We reviewed 143 patients with nasopharyngeal cancer who underwent 18F-FDG PET within 6 months after completion of radiotherapy between 2001 and 2012. 18F-FDG PET findings at the primary tumor (T–) and regional lymph nodes (N–) were separately assessed and considered negative [PET (–)] or positive [PET (+)] depending on the remaining focal increased uptake of 18F-FDG that was greater than that of the surrounding muscle or blood vessels. The standard of reference was histopathological confirmation or clinical/imaging follow-up. Overall survival (OS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRRFS) rates were estimated from the date of the start of radiotherapy.Results:The median follow-up period was 73 months (range, 9–182 months). Overall, 83 and 66% of patients achieved T–PET (-) and N–PET (-) responses, and the negative-predictive values (NPVs) for T– and N– were 100 and 99%, respectively. The sensitivity, specificity, and positive-predictive value were 100, 84, and 8% for T–, and 67, 80, and 7% for N–, respectively. The 5-year OS, DMFS, and LRRFS rates were 83, 83, and 87%, respectively, and patients with N–PET (+) with SUVmax >2.5 showed significantly inferior 5-year OS and DMFS rates than patients with N–PET (-) or N–PET (+) with SUVmax ≤2.5 (44 vs 86%, p = 0.004; 36 vs 85%, p < 0.001).Conclusion:In patients that have received definitive (chemo)radiotherapy for nasopharyngeal cancer, 18F-FDG PET within 6 months of completion of treatment has a high NPV for predicting residual disease and is prognostic for long-term treatment outcomes. Patients with remaining focal increased uptake of 18F-FDG at lymph nodes may benefit from more aggressive treatments, and further studies are needed to validate the clinical significance of post-radiotherapy 18F-FDG PET.Advances in knowledge:We found that post-radiotherapy 18F-FDG PET findings have a high NPV for detecting residual disease and are a significant prognostic factor for treatment outcomes.