Radiotherapy Combined with PD-1 Inhibition Increases NK Cell Cytotoxicity towards Nasopharyngeal Carcinoma Cells.
Ontology highlight
ABSTRACT: Background
Nasopharyngeal carcinoma (NPC) in endemic regions and younger patients is characterized by a prominent lymphomononuclear infiltration. Radiation is the principal therapeutic modality for patients with NPC. Recent data suggest that the efficacy of radiotherapy in various cancers can be augmented when combined with immune checkpoint blockade. Here, we investigate the effect of radiotherapy on the killing of NPC cells by Natural Killer (NK) cells.Methods
NPC cell lines and a patient-derived xenograft were exposed to NK cells in the context of radiotherapy. Cytotoxicity was measured using the calcein-release assay. The contribution of the PD-L1/PD-1 checkpoint and signaling pathways to killing were analyzed using specific inhibitors.Results
Radiotherapy sensitized NPC cells to NK cell killing and upregulated expression of PD-1 ligand (PD-L1) in NPC cells and PD-1 receptor (PD-1) in NK cells. Blocking of the PD-L1/PD-1 checkpoint further increased the killing of NPC cells by NK cells in the context of radiotherapy.Conclusion
Radiation boosts the killing of NPC cells by NK cells. Killing can be further augmented by blockade of the PD-L1/PD-1 checkpoint. The combination of radiotherapy with PD-L1/PD-1 checkpoint blockade could therefore increase the efficacy of radiotherapy in NPC tumors.
SUBMITTER: Makowska A
PROVIDER: S-EPMC8470143 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundNasopharyngeal carcinoma (NPC) is a highly malignant epithelial cancer linked to Epstein-Barr virus (EBV) infection. Tumors are characterized by a lymphomononuclear infiltrate and the number of natural killer (NK) cells in tumors appears to be of prognostic significance. Standard treatment for NPC in adolescents and young adults consists of induction chemotherapy followed by radiochemotherapy. Though survival rates are above 80%, the majority of patients suffer from long-term side-effects, mainly related to radiotherapy. The addition of immunotherapy to induction chemotherapy could improve tumor response.MethodsWe have investigated the killing of NPC cells by NK cells in the context of chemotherapy, using a panel of three nasopharyngeal carcinoma cell lines and a patient-derived xenograft. Cytotoxicity was measured using the calcein-release assay, while the contribution of different checkpoints and signaling pathways to killing was studied by siRNA-mediated gene silencing and chemical inhibitors.ResultsChemotherapeutics cisplatin, 5-fluorouracil and gemcitabine sensitized NPC cells to killing by NK cells. Chemotherapeutics led to upregulation of PD-1 in NK cells and PD-L1 in NPC cells via NF-κB. Inhibition of the PD-L1/PD-1 checkpoint by an anti-PD-1 antibody or siRNA increased NK-cell cytotoxicity towards NPC cells.ConclusionThe addition of an anti-PD-1 antibody to chemotherapy in patients with NPC could increase the efficacy of induction chemotherapy. If confirmed in a clinical trial, more efficient induction therapy could allow the dose of radiotherapy to be reduced and thereby diminish severe late effects of such therapy.
| S-EPMC7889576 | biostudies-literature
Project description:BackgroundThe present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC).MethodsPatients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint.ResultsA total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011).ConclusionRadiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.
| S-EPMC8620547 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a highly malignant epithelial cancer linked to EBV infection. Addition of interferon-β (IFNβ) to chemo- and radiochemotherapy has led to survival rates >90% in children and adolescents. As NPC cells are sensitive to apoptosis via tumor necrosis factor-related apoptosis inducing ligand (TRAIL), we explored the role of TRAIL and IFNβ in the killing of NPC cells by natural killer (NK) cells. NPC cells, including cells of a patient-derived xenograft were exposed to NK cells in the presence or absence of IFNβ. NK cells killed NPC- but not nasoepithelial cells and killing was predominately mediated via TRAIL. Incubation of NK cells with IFNβ increased cytotoxicity against NPC cells. Concomitant incubation of NK- and NPC cells with IFNβ before coculture reduced cytotoxicity and could be overcome by blocking the PD-1/PD-L1 axis leading to the release of intracellular TRAIL from NK cells. In conclusion, combination of IFNβ and anti-PD-1, augmenting cytotoxicity of NK cells against NPC cells, could be a strategy to improve NPC-directed therapy and warrants further evaluation in vivo.
| S-EPMC6617170 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a malignancy with unique clinical biological profiles such as associated Epstein-Barr virus infection and high radiosensitivity. Radiotherapy has long been recognized as the mainstay for the treatment of NPC. However, the further efficacy brought by radical radiotherapy has reached the bottleneck in advanced patients, who are prone to develop recurrence and distant metastasis after treatment. The application of photon therapy makes it possible for radiation dose escalation in refractory cases and may provide second chance for recurrent patients with less unrecoverable tissue damage. The concept of adaptive radiotherapy is put forward in consideration of target volume shrinkage during treatment. The replanning procedure offers better protection for the organ at risk. However, the best timing and candidates for adaptive radiotherapy is still under debate. The current tendency of artificial intelligence in NPC mainly focuses on image recognition, auto-segmentation and dose prediction. Although artificial intelligence is still in developmental stage, the future of it is promising.To further improve the efficacy of NPC, multimodality treatment is encouraged. In-depth studies on genetic and epigenetic variations help to explain the great heterogeneity among patients, and could further be applied to precise screening and prediction, personalized radiotherapy and the evolution of targeted drugs. Given the clinical benefit of immunotherapy in other cancers, the application of immunotherapy, especially immune checkpoint inhibitor, in NPC is also of great potential. Results from ongoing clinical trials combining immunotherapy with radiotherapy in NPC are expected.
| S-EPMC6774595 | biostudies-literature
Project description:BackgroundDefinitive chemoradiotherapy (CRT) is standard of care for nasopharyngeal carcinoma. Due to the tumor localization and concomitant platinum-based chemotherapy, hearing impairment is a frequent complication, without defined dose-threshold. In this study, we aimed to achieve the maximum possible cochleae sparing.Materials and methodsTreatment plans of 20 patients, treated with CRT (6 IMRT and 14 VMAT) based on the QUANTEC organs-at-risk constraints were investigated. The cochleae were re-delineated independently by two radiation oncologists, whereas target volumes and other organs at risk (OARs) were not changed. The initial plans, aiming to a mean cochlea dose < 45 Gy, were re-optimized with VMAT, using 2-2.5 arcs without compromising the dose coverage of the target volume. Mean cochlea dose, PTV coverage, Homogeneity Index, Conformity Index and dose to other OAR were compared to the reference plans. Wilcoxon signed-rank test was used to evaluate differences, a p value < 0.05 was considered significant.ResultsThe re-optimized plans achieved a statistically significant lower dose for both cochleae (median dose for left and right 14.97 Gy and 18.47 Gy vs. 24.09 Gy and 26.05 Gy respectively, p < 0.001) compared to the reference plans, without compromising other plan quality parameters. The median NTCP for tinnitus of the most exposed sites was 11.3% (range 3.52-91.1%) for the original plans, compared to 4.60% (range 1.46-90.1%) for the re-optimized plans (p < 0.001). For hearing loss, the median NTCP of the most exposed sites could be improved from 0.03% (range 0-99.0%) to 0.00% (range 0-98.5%, p < 0.001).ConclusionsA significantly improved cochlea sparing beyond current QUANTEC constraints is feasible without compromising the PTV dose coverage in nasopharyngeal carcinoma patients treated with VMAT. As there appears to be no threshold for hearing toxicity after CRT, this should be considered for future treatment planning.
| S-EPMC8017833 | biostudies-literature
Project description:Background: It remains controversial whether the application of chemotherapy has an impact on recurrent nasopharyngeal carcinoma (rNPC) patients with salvage radiotherapy. Here, we aimed to evaluate treatment outcomes of rNPC patients and derive a prognostic model to assess the benefit of chemotherapy in patients with re-radiotherapy. Methods: This study was conducted as a retrospective study. In total, 340 rNPC patients treated with salvage intensity-modulated radiotherapy (IMRT) or radiochemotherapy (RCT) from October 2006 to September 2019 were included in this study. Overall survival (OS) was the primary outcome. Kaplan-Meier method was employed to detect the prognostic difference with Log-rank tests. The Cox regression analysis was performed to explore the potential prognostic factors while the multivariate Cox analysis was used to identify candidate variables for the prognostic model of OS. Results: The 5-year actuarial rates of OS, progression-free survival, loco-regional progression-free survival, and distant metastases-free survival did not show significant difference between the IMRT and RCT groups (P > .05). Age at recurrence and rT category were found to be the independent prognostic factors for OS. We found that rNPC patients suffered poor OS in the high-risk group (patients with higher age at recurrence and advanced rT category) (high-risk vs low-risk, HR = 1.87, 95% CI: 1.36-2.57, P < .001). Salvage RT alone may be superior to RCT for patients in the low-risk group (RCT group vs RT group, HR = 1.89, 95% CI: 1.11-3.20, P = .038). Conclusion: Salvage RT combined with chemotherapy cannot improve survival outcomes for rNPC. More novel clinical trials should be explored to develop individualized strategies to improve survival and minimize toxicities.
| S-EPMC9926007 | biostudies-literature
Project description:BackgroundPrevious studies have explored cancer immunotherapy with radiotherapy or anti-angiogenic therapy, but no trials have reported a triple therapy approach. This study aimed to investigate safety and clinical outcome of PD-1/PD-L1 inhibitors combined with palliative radiotherapy and targeted angiogenesis therapy in hepatocellular carcinoma (HCC) of Barcelona Clinic Liver Cancer (BCLC) stage C.MethodsConsecutive patients (n=16) treated with PD-1/PD-L1 inhibitors combined with radiotherapy and anti-angiogenic therapy in a bi-institutional cohort between July 2017 and December 2020 were retrospectively included. Radiotherapy was conducted within 14 days of the first administration of immunotherapy. The primary endpoint was treatment-related adverse event (TRAE).ResultsThe median follow-up was 383 days. Fifteen patients (93.8%) experienced at least 1 TRAE. The most common TRAEs of any grade were rash (25%), diarrhea (25%), aspartate aminotransferase increase (18.8%), alanine transaminase increase (18.8%), decreased appetite (18.8%), and fatigue (18.8%). Grade 3/4 TRAEs occurred in 4 patients (25%) and finally led to treatment interruption. No patient death was attributed to treatment. No specific events were responsible for the addition of radiotherapy. Six patients showed partial response, 7 showed stable disease, and 2 showed progressive disease. The objective response rate and disease control rate were 40.0% (95% CI 16.3%-67.7%) and 86.7% (95% CI 59.5%-98.3%), respectively. Moreover, the median progression-free survival was 140 days. Patients had a median overall survival of 637 days, and the estimated rates of survival at 6 and 12 months were 92.3% and 75.5%, respectively.ConclusionPD-1/PD-L1 inhibitors combined with palliative radiotherapy and anti-angiogenic therapy appear to be safe, with no unexpected adverse events. Additional studies exploring the clinical benefit are warranted.
| S-EPMC8170410 | biostudies-literature
Project description:BackgroundHead and neck squamous cell carcinomas (HNSCC) are malignant neoplasms with poor prognosis. Treatment-resistant cancer stem cell (CSC) is one reason for treatment failure. Considerable attention has been focused on sulforaphane (SF), a phytochemical from broccoli possessing anticancer properties. We investigated whether SF could enhance the chemotherapeutic effects of cisplatin (CIS) and 5-fluorouracil (5-FU) against HNSCC-CSCs, and its mechanisms of action.MethodsCD44+/CD271+ FACS-isolated CSCs from SCC12 and SCC38 human cell lines were treated with SF alone or combined with CIS or 5-FU. Cell viability, colony- and sphere-forming ability, apoptosis, CSC-related gene and protein expression and in vivo tumour growth were assessed. Safety of SF was tested on non-cancerous stem cells and in vivo.ResultsSF reduced HNSCC-CSC viability in a time- and dose-dependent manner. Combining SF increased the cytotoxicity of CIS twofold and 5-FU tenfold, with no effects on non-cancerous stem cell viability and functions. SF-combined treatments inhibited CSC colony and sphere formation, and tumour progression in vivo. Potential mechanisms of action included the stimulation of caspase-dependent apoptotic pathway, inhibition of SHH pathway and decreased expression of SOX2 and OCT4.ConclusionsCombining SF allowed lower doses of CIS or 5-FU while enhancing these drug cytotoxicities against HNSCC-CSCs, with minimal effects on healthy cells.
| S-EPMC7591858 | biostudies-literature
Project description:The small-molecule inhibitor of p53-Mdm2 interaction, Nutlin-3, is known to be effective against cancers expressing wild-type (wt) p53. p53 mutations are rare in nasopharyngeal carcinoma (NPC), hence targeting disruption of p53-Mdm2 interaction to reactivate p53 may offer a promising therapeutic strategy for NPC. In the present study, the effects of Nutlin-3 alone or in combination with cisplatin, a standard chemotherapeutic agent, were tested on C666-1 cells, an Epstein-Barr virus (EBV)-positive NPC cell line bearing wt p53. Treatment with Nutlin-3 activated the p53 pathway and sensitized NPC cells to the cytotoxic effects of cisplatin. The combined treatment also markedly suppressed soft agar colony growth formation and increased apoptosis of NPC cells. The effect of Nutlin-3 on NPC cells was inhibited by knockdown of p53, suggesting that its effect was p53-dependent. Extended treatment with increasing concentrations of Nutlin-3 did not result in emergence of p53 mutations in the C666-1 cells. Collectively, the present study revealed supportive evidence of the effectiveness of combining cisplatin and Nutlin-3 as a potential therapy against NPC.
| S-EPMC4564086 | biostudies-literature
Project description:The present study aimed to retrospectively analyze the survival outcomes and prognostic factors for patients with nasopharyngeal carcinoma (NPC) receiving intensity-modulated radiotherapy (IMRT).Clinical data was collected from 691 patients with NPC receiving IMRT from January 2009 to August 2015. A survival analysis was performed and prognostic factors were analyzed using the Kaplan-Meier method, the Cox proportional hazards regression model, and the log-rank test.The median follow-up time was 62.8 months. Sixty-three patients experienced relapse, 44 cases (70%) of which occurred within 3 years. Six cases (9.5%) remained in remission for over 5 years. Seventy-two patients developed metastasis, 63 cases (87.5%) of which occurred within 3 years and only 1 case occurred after 5 years (1.3%). Five-year disease special survival (DSS), progression free survival, locoregional recurrence free survival, and distant metastasis free survival were 86.5%, 82.5%, 90.7%, and 89.4%, respectively in patients with NPC. Patients with stage III NPC with and without induction chemotherapy had 5-year DSS rates of 95.8% and 89.3%, respectively (P?=?.00). Patients with stage IVa NPC with and without induction chemotherapy had 5-year DSS rates of 73.1% and 68.9%, respectively (P?=?.04). The 5-year DSS rates of patients with stage III with or without concurrent chemotherapy were 92.8% and 85.5%, respectively (P?=?.04). The 5-year DSS rates of patients with stage IV with or without concurrent chemotherapy were 72.7% and 53.0% (P?=?.02).IMRT improves the survival rate of patients with NPC. Recurrence and metastasis mainly occur within 2 to 3 years after radiotherapy. Induction and concurrent chemotherapy improve the 5-year DSS of patients with locally advanced NPC.
| S-EPMC7386990 | biostudies-literature