Radiomics signature for dynamic changes of tumor-infiltrating CD8+ T cells and macrophages in cervical cancer during chemoradiotherapy.

BACKGROUND: Our previous study suggests that tumor CD8+ T cells and macrophages (defined as CD68+ cells) infiltration underwent dynamic and heterogeneous changes during concurrent chemoradiotherapy (CCRT) in cervical cancer patients, which correlated with their short-term tumor response. This study aims to develop a CT image-based radiomics signature for such dynamic changes. METHODS: Thirty cervical squamous cell carcinoma patients, who were treated with CCRT followed by brachytherapy, were included in this study. Pre-therapeutic CT images were acquired. And tumor biopsies with immunohistochemistry at primary sites were performed at baseline (0 fraction (F)) and immediately after 10F. Radiomics features were extracted from the region of interest (ROI) of CT images using Matlab. The LASSO regression model with ten-fold cross-validation was utilized to select features and construct an immunomarker classifier and a radiomics signature. Their performance was evaluated by the area under the curve (AUC). RESULTS: The changes of tumor-infiltrating CD8+T cells and macrophages after 10F radiotherapy as compared to those at baseline were used to generate the immunomarker classifier (AUC= 0.842, 95% CI:0.680-1.000). Additionally, a radiomics signature was developed using 4 key radiomics features to predict the immunomarker classifier (AUC=0.875, 95% CI:0.753-0.997). The patients stratified based on this signature exhibited significant differences in treatment response (p = 0.004). CONCLUSION: The radiomics signature could be used as a potential predictor for the CCRT-induced dynamic alterations of CD8+ T cells and macrophages, which may provide a less invasive approach to appraise tumor immune status during CCRT in cervical cancer compared to tissue biopsy.

Radiotherapy for patients with esophageal cancer aged 80 years or older: A 16-year experience.

PURPOSE: Radiotherapy (RT) plays an important role in esophageal cancer (EC) patients aged ≥80 years. However, the survival modality and prognostic factors remain poorly understood. Thus, this study aimed to evaluate the tolerance and long-term overall survival (OS) of patients aged ≥80 years who were diagnosed with EC and underwent definitive RT. MATERIALS AND METHODS: A total of 213 consecutive patients with EC over 80 years old who were treated with curative intent RT between February 1999 and December 2015 at our institution were retrospectively reviewed. The clinical prognostic variables were analyzed against OS in univariate analyses using log-rank tests and in a multivariate model using Cox regression proportional hazards analysis. RESULT: The median patient age was 82 (range: 80-94) years. Atotal of 192 patients (90.1%) completed the definitive RT (median: 60 Gy, range: 50-72 Gy), and 11 patients had grade 4 or higher acute toxicity, including esophagitis, a cardiac event, infections, and sudden death. Atotal of 168 deaths (78.9%) were observed with a median follow up of 47 months (range: 0-153 months). The OS rates were 50.3%, 17.6%, and 13.2% at 1, 3, and 5 years, respectively. Multivariable analysis identified that tumors located in the cervical and upper thorax, a shorter tumor lesion, RT treatment of 50-60Gy, and a better response to treatment were the factors associated with longer OS. CONCLUSION: Definitive RT could be considered as an effective treatment for patients with EC who are older than 80 years, and 50-60 Gy seems to be a reasonable dose for these patients.

Cone photoreceptor phosphodiesterase PDE6H inhibition regulates cancer cell growth and metabolism, replicating the dark retina response.

BACKGROUND: PDE6H encodes PDE6γ', the inhibitory subunit of the cGMP-specific phosphodiesterase 6 in cone photoreceptors. Inhibition of PDE6, which has been widely studied for its role in light transduction, increases cGMP levels. The purpose of this study is to characterise the role of PDE6H in cancer cell growth. METHODS: From an siRNA screen for 487 genes involved in metabolism, PDE6H was identified as a controller of cell cycle progression in HCT116 cells. Role of PDE6H in cancer cell growth and metabolism was studied through the effects of its depletion on levels of cell cycle controllers, mTOR effectors, metabolite levels, and metabolic energy assays. Effect of PDE6H deletion on tumour growth was also studied in a xenograft model. RESULTS: PDE6H knockout resulted in an increase of intracellular cGMP levels, as well as changes to the levels of nucleotides and key energy metabolism intermediates. PDE6H knockdown induced G1 cell cycle arrest and cell death and reduced mTORC1 signalling in cancer cell lines. Both knockdown and knockout of PDE6H resulted in the suppression of mitochondrial function. HCT116 xenografts revealed that PDE6H deletion, as well as treatment with the PDE5/6 inhibitor sildenafil, slowed down tumour growth and improved survival, while sildenafil treatment did not have an additive effect on slowing the growth of PDE6γ'-deficient tumours. CONCLUSIONS: Our results indicate that the changes in cGMP and purine pools, as well as mitochondrial function which is observed upon PDE6γ' depletion, are independent of the PKG pathway. We show that in HCT116, PDE6H deletion replicates many effects of the dark retina response and identify PDE6H as a new target in preventing cancer cell proliferation and tumour growth.

LncRNA WAC-AS1 promotes osteosarcoma Metastasis and stemness by sponging miR-5047 to upregulate SOX2.

Cancer stemness and osteosarcoma (OS) malignant progression are closely associated. However, the molecular mechanisms underlying this association have not been fully demonstrated. Long noncoding RNAs (lncRNAs) are an intriguing class of widely prevalent endogenous RNAs involved in OS progression, the vast majority of which have not been characterized functionally. Here, we identified tumor promoter lncRNA WAC-AS1 to be highly expressed in OS tumors and associated with worse survival. Further analysis revealed that WAC-AS1 increased tumorsphere formation of OS cells and promoted metastasis, as confirmed by cell proliferation, transwell and wound healing assays. MiR-5047 was identified as a downstream target of WAC-AS1. Subsequently, based on bioinformatics analysis, RIP assay and luciferase reporter assay, SOX2 mRNA was verified as a target of miR-5047. WAC-AS1 enhanced OS cell proliferation and stemness via acting as a ceRNA by binding to miR-5047, thereby increasing SOX2 expression. In addition, SOX2 bound to the promoter region of WAC-AS1 and promoted its transcription, thereby forming a positive feedback loop to regulate OS malignancy. Taken together, our findings show WAC-AS1 is a tumor promoter and a key regulator of OS cell stemness and metastasis via a miR-5047/SOX2 axis.

A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.

Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4ß7+CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4ß7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4ß7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.

Natural progression of persistent pure ground-glass nodules 10 mm or smaller: long-term observation and risk factor assessment.

PURPOSE: Semi-automatic segmentation was used to investigate the natural progression of pure ground-glass nodules (pGGNs) of 5-10 mm in long-term follow-up and to analyze independent risk factors for subsequent growth. MATERIALS AND METHODS: A total of 154 pGGNs of 5-10 mm from 132 patients with 698 follow-up CT scans were retrospectively identified. Subsequently, enrolled pGGNs were semiautomatically segmented on initial and follow-up CT to obtain diameter, density and volume, thus calculating mass, volume doubling time (VDT), and mass doubling time (MDT). Kaplan‒Meier analysis and multivariate Cox proportional risk regression were performed to explore independent predictors of pGGN growth. We analyzed growth differences among different pathological results of pGGNs confirmed by surgery. The prognosis was analyzed using the total diameter or solid size of the nodules on the last preoperative CT. RESULTS: Among the 85 (55.2%) pGGNs with growth, 5.9%, 51.8%, and 80.0% showed growth within 1, 3, and 5 years, respectively. The median VDT and MDT were 1206.4 (range 349.8-5134.4) days and 1161.3 (range 339.4-6630.4) days, respectively. The multivariate Cox risk regression analysis showed that mean CT attenuation (m-CTA) [hazard ratio (HR) = 2.098, p = 0.010] and roundness index (HR = 1.892, p = 0.021) were independent risk factors for pGGN growth. In total, 67.6% of surgically resected and growing pGGNs were invasive non-mucinous adenocarcinoma (IA), including 2 cases of endpoint events, showing a PSN with solid components of 5.6 mm and a solid nodule with a diameter of 19.9 mm. CONCLUSIONS: pGGNs of 5-10 mm showed an indolent clinical course. Follow-up CT imaging of pGGNs in the latter half of the first two years should be a rational management strategy. Small pGGNs with a larger overall m-CTA and roundness index on baseline CT are more likely to grow.

Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.

Radiomics models based on CT at different phases predicting lymph node metastasis of esophageal squamous cell carcinoma (GASTO-1089).

Purpose: To investigate the value of radiomics models based on CT at different phases (non-contrast-enhanced and contrast-enhanced images) in predicting lymph node (LN) metastasis in esophageal squamous cell carcinoma (ESCC). Methods and materials: Two hundred and seventy-four eligible patients with ESCC were divided into a training set (n =193) and a validation set (n =81). The least absolute shrinkage and selection operator algorithm (LASSO) was used to select radiomics features. The predictive models were constructed with radiomics features and clinical factors through multivariate logistic regression analysis. The predictive performance and clinical application value of the models were evaluated by area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA). The Delong Test was used to evaluate the differences in AUC among models. Results: Sixteen and eighteen features were respectively selected from non-contrast-enhanced CT (NECT) and contrast-enhanced CT (CECT) images. The model established using only clinical factors (Model 1) has an AUC value of 0.655 (95%CI 0.552-0.759) with a sensitivity of 0.585, a specificity of 0.725 and an accuracy of 0.654. The models contained clinical factors with radiomics features of NECT or/and CECT (Model 2,3,4) have significantly improved prediction performance. The values of AUC of Model 2,3,4 were 0.766, 0.811 and 0.809, respectively. It also achieved a great AUC of 0.800 in the model built with only radiomics features derived from NECT and CECT (Model 5). DCA suggested the potential clinical benefit of model prediction of LN metastasis of ESCC. A comparison of the receiver operating characteristic (ROC) curves using the Delong test indicated that Models 2, 3, 4, and 5 were superior to Model 1(P< 0.05), and no difference was found among Model 2, 3, 4 and Model 5(P > 0.05). Conclusion: Radiomics models based on CT at different phases could accurately predict the lymph node metastasis in patients with ESCC, and their predictive efficiency was better than the clinical model based on tumor size criteria. NECT-based radiomics model could be a reasonable option for ESCC patients due to its lower price and availability for renal failure or allergic patients.

Inhibitory Effect of Trihydroxy Isoflavone on Neuronal Apoptosis in Natural Aging Rats.

Objective: To explore the impact of genistein (Gen) on the apoptosis of neuronal cells in naturally aged rats and its mechanism. Methods: Fifty SD male rats were allocated into five groups at random, including youth group (3M group), natural aging group (24M group), and Gen low-, medium-, and high-dose groups. Starting from 18 months of age, Gen 10, 30, and 60 mg-kg-1 were administered via gavage to the Gen low-, medium-, and high-dose groups, respectively, while the rats in the natural aging group was given saline by gavage until 24 months of age, and the drug was stopped for 1 d per week for 6 months. The protein expression of target genes was examined using western blotting. Results: In contrast to the 3M group, the 24M group rats showed disturbed neuronal cell arrangement and massive cell degeneration. After 6 months of Gen intervention, in contrast to the 24M group, the neural cell pathology in the CA3 area of the hippocampus improved and cell apoptotic decreased observably. In contrast to the 3M group, the protein expression of c-Jun amino-terminal kinase (p-JNK), C/EBP homologous protein (CHOP), inflammatory vesicle 3-associated factor (NLRP3), cysteine protease-1 (Caspase-1), and apoptosis-related punctate protein (ASC) and downstream inflammatory factors in the hippocampus was obviously increased in the 24M group. In contrast to the 24M group, the protein expression of p-JNK, CHOP, NLRP3, Caspase-1, and ASC and downstream inflammatory factors in the hippocampus was observably declined in Gen groups. Conclusion: Gen has a protective effect on hippocampal neurons in aging rat brain tissue via the inhibition of the ERS apoptotic signaling pathway and NLRP3 inflammatory vesicle activation.

Endothelial cell death after ionizing radiation does not impair vascular structure in mouse tumor models.

The effect of radiation therapy on tumor vasculature has long been a subject of debate. Increased oxygenation and perfusion have been documented during radiation therapy. Conversely, apoptosis of endothelial cells in irradiated tumors has been proposed as a major contributor to tumor control. To examine these contradictions, we use multiphoton microscopy in two murine tumor models: MC38, a highly vascularized, and B16F10, a moderately vascularized model, grown in transgenic mice with tdTomato-labeled endothelium before and after a single (15 Gy) or fractionated (5 × 3 Gy) dose of radiation. Unexpectedly, even these high doses lead to little structural change of the perfused vasculature. Conversely, non-perfused vessels and blind ends are substantially impaired after radiation accompanied by apoptosis and reduced proliferation of their endothelium. RNAseq analysis of tumor endothelial cells confirms the modification of gene expression in apoptotic and cell cycle regulation pathways after irradiation. Therefore, we conclude that apoptosis of tumor endothelial cells after radiation does not impair vascular structure.

A reduction of Syndecan-4 in macrophages promotes atherosclerosis by aggravating the proinflammatory capacity of macrophages.

BACKGROUND: Cardiovascular diseases (CVDs) are a significant cause of mortality worldwide and are characterized by severe atherosclerosis (AS) in patients. However, the molecular mechanism of AS formation remains elusive. In the present study, we investigated the role of syndecan-4 (SDC4), a member of the syndecan family, in atherogenesis. METHODS AND RESULTS: The expression of SDC4 decreased in mouse severe AS models. Moreover, knockout of SDC4 accelerated high-cholesterol diets (HCD)-induced AS in ApoE-/- mice. Mechanistically, the decrease of SDC4 increased macrophage proinflammatory capacity may be through the PKCα-ABCA1/ABCG1 signaling pathway. CONCLUSION: These findings provide evidence that SDC4 reduction links macrophages and inflammation to AS and that SDC4 in macrophages provides a therapeutic target for preventing AS formation.

PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer.

Preclinical experimentation revealed that established cancers treated with the immunogenic cell death (ICD) inducer oxaliplatin are sensitized to immune checkpoint inhibitors targeting PD-1. In contrast, no such sensitizing effect is observed when cisplatin, a non-immunogenic cell death inducer is used. Two randomized phase III clinical trials targeting unresectable gastric and gastro-esophageal junction carcinomas apparently validate this observation. Thus, oxaliplatin-based chemotherapy (together with capecitabine or 5-fluorouracil plus leucovorin) favorably interacted with nivolumab, yielding improved outcome. In contrast, the outcome of cisplatin-based chemotherapy (together with capecitabine or 5-fluorouracil) failed to be improved by concomitant treatment with pembrolizumab. These clinical findings underscore the importance of choosing appropriate ICD-inducing cytotoxicants for the development of chemoimmunotherapeutic regimens. Unfortunately, the FDA and EMA have approved PD-1 blockade in combination with "platinum-based chemotherapy" without specifying the precise nature of the platinum-containing drug. This is a non sequitur. Based on the available clinical data, such approvals should be restricted to the use of oxaliplatin.

Major vault protein attenuates cardiomyocyte injury in doxorubicin-induced cardiomyopathy through activating AKT.

BACKGROUND: Doxorubicin (DOX) has limited chemotherapy application for malignancies due to cardiotoxicity. The pathogenesis of DOX-induced cardiomyopathy (DiCM) is yet to be elucidated. Increasing studies proved that activation of AKT prevented cardiomyocyte apoptosis and cardiac dysfunction in response to DOX insult. Our previous studies indicated that major vault protein (MVP) deficiency was accompanied by suppressed phosphorylation of AKT in metabolic diseases. This study aimed to investigate the role and underlying mechanism of MVP on cardiomyocyte apoptosis in DiCM. METHODS: Mice were intraperitoneally injected with DOX 5 mg/kg, once a week for 5 weeks, the total cumulative dose was 25 mg/kg. Cardiomyocyte-specific MVP overexpression was achieved using an adeno-associated virus system under the cTnT promoter after the fourth DOX injection. Cardiac function was examined by echocardiography followed by euthanasia. Tissue and serum were collected for morphology analysis and biochemical examination. RESULTS: Herein, we found that MVP expression was upregulated in DOX-treated murine hearts. Cardiac-specific MVP overexpression alleviated DOX-induced cardiac dysfunction, oxidative stress and fibrosis. Mechanistically, MVP overexpression activated AKT signaling and decreased cardiomyocyte apoptosis in DiCM. CONCLUSIONS: Based on these findings, we supposed that MVP was a potential therapeutic agent against DiCM.

Percutaneous intravenous catheter forceps biopsy in right atrial mass: two case reports and literature review.

BACKGROUND: Primary malignant tumors of the heart are rare. Although preoperative histological diagnosis is difficult, it has paramount value in therapeutic strategy development and prognostic estimation. Herein, we reported 2 cases of intracardiac tumors. CASES PRESENTATION: Both patients presented to the hospital with heart-related symptoms. Echocardiography showed massive masses in the atrium and positron emission tomography-computed tomography (PET/CT) revealed hypermetabolism and invasiveness. One patient cannot take surgery due to extensive metastasis and poor condition. The other patient was primarily diagnosed with lymphoma, and surgery was not recommended. They successfully underwent intravenous atrial biopsy, and histological samples confirmed intimal sarcoma and diffuse large B cell lymphoma. Based on immunohistochemical and molecular assessments, targeted chemotherapy was administered, resulting in clinical and imaging remission at discharge. CONCLUSIONS: Percutaneous intravenous catheter biopsy as a safe invasive test provides an accurate pathological diagnosis after imaging evaluation, and offers a therapeutic direction. Nonmalignant masses and some chemo-radiosensitive malignant tumors in the atrium could have good prognosis after targeted therapy.

Late Toxicities, Failure Patterns, Local Tumor Control, and Survival of Esophageal Squamous Cell Carcinoma Patients After Chemoradiotherapy With a Simultaneous Integrated Boost: A 5-Year Phase II Study.

PURPOSE: We aimed to evaluate the long-term outcomes of concurrent chemoradiotherapy (CCRT) with a simultaneous integrated boost (SIB) of radiotherapy for esophageal squamous cell carcinoma (ESCC). METHODS AND MATERIALS: Eighty-seven patients with primary ESCC enrolled in this phase II trial. The majority (92.0%) had locoregionally advanced disease. They underwent definitive chemoradiotherapy. The radiotherapy doses were 66 Gy for the gross tumor and 54 Gy for the subclinical disease. Doses were simultaneously administered in 30 fractions over 6 weeks. The patients also underwent concurrent and adjuvant chemotherapy, which comprised cisplatin and fluorouracil. The study end points were acute and late toxicities, first site of failure, locoregional tumor control, and overall survival rates. RESULTS: The median follow-up time was 65.7 (range, 2.2-97.5) months for all patients and 81.5 (range, 19.4-97.5) months for those alive. There were 17 cases (19.5%) of severe late toxicities, including four cases (4.6%) of grade 5 and seven (8.0%) of grade 3 esophageal ulceration, four (4.6%) of grade 3 esophageal stricture, and two (2.3%) of grade 3 radiation-induced pneumonia. Twenty-three (26.4%) patients had locoregional disease progression. Most (86.7%) locally progressive lesions were within the dose-escalation region in the initial radiation plan, while majority of the recurrent lymph nodes were found out-of-field (83.3%) and in the supraclavicular region (75.0%). The 1-, 2-, 3-, and 5-year locoregional tumor control and overall survival rates were 79.2%, 72.4%, 72.4%, 70.8%, and 82.8%, 66.6%, 61.9%, 58.4%, respectively. Incomplete tumor response, which was assessed immediately after CCRT was an independent risk predictor of disease progression and death in ESCC patients. CONCLUSIONS: CCRT with SIB was well tolerated in ESCC patients during treatment and long-term follow-up. Moreover, patients who underwent CCRT with SIB exhibited improved local tumor control and had better survival outcomes compared to historical data of those who had standard-dose radiotherapy.

Distribution of Peripheral Blood Cells in Esophageal Cancer Patients During Concurrent Chemoradiotherapy Predicts Long-Term Locoregional Progression Hazard After Treatment (GASTO1072).

PURPOSE: Predicting the response to chemoradiotherapy is critical for the optimal management of esophageal cancer; however, it remains an unmet clinical need. This study aimed to evaluate the predictive potential of peri-treatment peripheral blood cells (PBC) in disease progression hazard in esophageal cancer following chemoradiotherapy. PATIENTS AND METHODS: A total of 87 patients with primary esophageal squamous cell carcinoma were subjected to definitive concurrent chemoradiotherapy in a Phase II trial. PBC parameters (hemoglobin, neutrophils, platelets, lymphocytes, and monocytes) were collected at seven time points throughout the course of radiotherapy. The potential of peri-treatment PBC parameters to predict the 3-year cumulative hazard of tumor progression was evaluated. RESULTS: Patients with disease progression displayed distinct distribution patterns of peri-treatment PBC compared to that in patients without disease progression. Greater prediction capabilities for risk of locoregional disease progression were found in PBC collected after the start of radiotherapy compared to those in their pretreatment counterparts, and in individual parameters rather than cell-to-cell ratios. The most predictive PBC parameters were integrated by summation and designated as a PBC score (PBCS), which further augmented their predictive power. Patients classified according to their PBCS (high vs medium v. low) had significantly different 3-year cumulative hazards of locoregional progression (58% vs 29% vs 7%, P = 0.0017). Multivariate analysis confirmed that high PBCS (HR, 12.2; 95% CI, 2.0-76.3; P = 0.007) and medium (HR, 5.8; 95% CI 1.2-27.7; P = 0.028) were independent indicators of locoregional progression. CONCLUSION: Systematic analysis of PBC distribution in esophageal cancer patients undergoing definitive chemoradiotherapy could help predict long-term locoregional progression hazard after treatment.

Heterogeneity of IFN-Mediated Responses and Tumor Immunogenicity in Patients with Cervical Cancer Receiving Concurrent Chemoradiotherapy.

PURPOSE: To ask whether the expression of immune markers and IFN signaling in tumor biopsies changes during concurrent chemoradiotherapy (CCRT). EXPERIMENTAL DESIGN: Tumor biopsies and peripheral mononuclear blood cells (PMBC) before and immediately after 20 Gy/10 fractions (F) of radiation treatment (RT) from 30 patients with cervical cancer receiving CCRT were evaluated by IHC and qRT-PCR for immune markers and correlated with the short-term response. RESULTS: Tumor immune response to radiation before and after 10F RT as reflected by CD8+ T-cell infiltration had substantial heterogeneity with increases, decreases, and no change all evident. Increases in CD8+ T cells during CCRT correlated with the presence of nuclear IRF1 in tumor cells (r = 0.68, P < 0.0001) and the patient short-term response (P < 0.01). Similarly, in a subset of patients (∼40%) PD-L1 positivity in tumor cells increased, which also correlated with nuclear IRF1 staining (r = 0.48, P < 0.01). Patients with augmented PMBC IFN signature expression after 10F had a significantly higher probability of PD-L1 induction (83% vs. 7%, P < 0.0001). Most patients exhibited abundant expression of SERPINB9 and CD47 in tumor cells, and tumor infiltration by CD68+ cells. SERPINB9 expression correlated with STAT1 signaling in tumor cells. CONCLUSIONS: CCRT leads to differential tumor immunogenicity and IFN signaling in patients with cervical cancer, suggesting radiation induction of immunity is limited to a subset of patients and may reflect the heterogeneity of intratumoral induction of IFNs.See related commentary by Mondini and Deutsch, p. 3815.

Imaging biomarkers of contrast-enhanced computed tomography predict survival in oesophageal cancer after definitive concurrent chemoradiotherapy.

BACKGROUND: This study aimed to evaluate the predictive potential of contrast-enhanced computed tomography (CT)-based imaging biomarkers (IBMs) for the treatment outcomes of patients with oesophageal squamous cell carcinoma (OSCC) after definitive concurrent chemoradiotherapy (CCRT). METHODS: Altogether, 154 patients with OSCC who underwent definitive CCRT were included in this retrospective study. All patients were randomised to the training cohort (n = 99) or the validation cohort (n = 55). Pre-treatment contrast-enhanced CT scans were obtained for all patients and used for the extraction of IBMs. An IBM score, was constructed by using the least absolute shrinkage and selection operator with Cox regression analysis, which was equal to the log-partial hazard of the Cox model in the training cohort and tested in the validation cohort. IBM nomograms were built based on IBM scores for individualised survival estimation. Finally, a decision curve analysis was performed to estimate the clinical usefulness of the nomograms. RESULTS: Altogether, 96 IBMs were extracted from each contrast-enhanced CT scan. IBM scores were constructed from 11 CT-based IBMs for overall survival (OS) and 8 IBMs for progression-free survival (PFS), using the LASSO-Cox regression method in the training cohort. Multivariate analysis revealed that IBM score was an independent prognostic factor correlated with OS and PFS. In the training cohort, the C-indices of IBM scores were 0.734 (95% CI 0.664-0.804) and 0.658 (95% CI 0.587-0.729) for OS and PFS, respectively. In the validation cohort, C-indices were 0.672 (95% CI 0.578-0.766) and 0.666 (95% CI 0.574-0.758) for OS and PFS, respectively. Kaplan-Meier survival analysis showed a significant difference between risk subgroups in the training and validation cohorts. Decision curve analysis confirmed the clinical usefulness of the IBM score. CONCLUSIONS: The IBM score based on pre-treatment contrast-enhanced CT could predict the OS and PFS for patients with OSCC after definitive CCRT. Further multicentre studies with larger sample sizes are warranted.

Deletion of the deISGylating enzyme USP18 enhances tumour cell antigenicity and radiosensitivity.

BACKGROUND: Interferon (IFN) signalling pathways, a key element of the innate immune response, contribute to resistance to conventional chemotherapy, radiotherapy, and immunotherapy, and are often deregulated in cancer. The deubiquitylating enzyme USP18 is a major negative regulator of the IFN signalling cascade and is the predominant human protease that cleaves ISG15, a ubiquitin-like protein tightly regulated in the context of innate immunity, from its modified substrate proteins in vivo. METHODS: In this study, using advanced proteomic techniques, we have significantly expanded the USP18-dependent ISGylome and proteome in a chronic myeloid leukaemia (CML)-derived cell line. USP18-dependent effects were explored further in CML and colorectal carcinoma cellular models. RESULTS: Novel ISGylation targets were characterised that modulate the sensing of innate ligands, antigen presentation and secretion of cytokines. Consequently, CML USP18-deficient cells are more antigenic, driving increased activation of cytotoxic T lymphocytes (CTLs) and are more susceptible to irradiation. CONCLUSIONS: Our results provide strong evidence for USP18 in regulating antigenicity and radiosensitivity, highlighting its potential as a cancer target.