Background:Extensive-stage small cell lung cancer (ES-SCLC) remains a highly aggressive malignancy with limited survival outcomes. While first-line immune checkpoint inhibitors combined with platinum-based chemotherapy have improved survival, the benefit is modest. Emerging evidence supports the integration of anti-angiogenic therapy and thoracic radiotherapy (TRT) to enhance systemic and local control. However, a comprehensive multimodal regimen combining chemotherapy, immunotherapy, anti-angiogenic therapy, and TRT has not been systematically evaluated. This study aims to assess the safety, feasibility, and preliminary efficacy of a multimodal treatment strategy involving induction with benmelstobart [an anti-programmed death-ligand 1 (PD-L1) antibody], platinum-etoposide chemotherapy, and anlotinib, followed by consolidation with benmelstobart, anlotinib, and sequential TRT in patients with untreated ES-SCLC. Methods:This is a prospective, single-center, single-arm, phase II, open-label trial conducted at Tianjin Medical University Cancer Institute & Hospital. Twenty-five patients with histologically confirmed, treatment-naive ES-SCLC and measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 will be enrolled. The regimen consists of-induction phase: 4 cycles of benmelstobart (1,200 mg IV q21d), carboplatin (area under the curve 5) or cisplatin (75-80 mg/m2) on day 1, etoposide (100 mg/m2 IV days 1-3), and oral anlotinib (12 mg once daily, 2 weeks on/1 week off); consolidation phase: 2 cycles of benmelstobart, anlotinib, and TRT (25 Gy in 5 daily fractions of 5 Gy each, administered only during the first consolidation cycle); maintenance phase: benmelstobart plus anlotinib until progression, unacceptable toxicity, or clinical deterioration. The co-primary endpoints are progression-free survival (PFS) and incidence of grade ≥3 treatment-related adverse events (TRAEs). Secondary endpoints include objective response rate and overall survival. Safety will be evaluated in all treated patients. Discussion:This trial will provide critical preliminary evidence on the safety, feasibility, and efficacy of integrating short-course TRT into a quadruple chemo-immuno-antiangiogenic backbone for ES-SCLC. The results are expected to inform the design of future multicenter, randomized phase III trials and potentially establish a novel multimodal paradigm for first-line management. Trial Registration:ClinicalTrials.gov identifier: NCT07358676. Protocol version: version 1.0, April 03, 2025.

Background:Neoadjuvant chemoimmunotherapy is standard for resectable stage III non-small cell lung cancer (NSCLC), yet reliable predictive biomarkers are lacking. Tertiary lymphoid structures (TLS) correlate with survival in NSCLC, but their role in predicting chemoimmunotherapy response remains unclear. This study aimed to characterize TLS comprehensively and develop a composite TLS score to predict pathological response and survival in stage III NSCLC. Methods:We retrospectively analyzed tumor tissues from patients with stage III (IIIA-IIIC) NSCLC who underwent neoadjuvant chemoimmunotherapy. TLS were characterized using hematoxylin and eosin (H&E) staining and multiplex immunohistochemistry (mIHC) for maturity, density, area, location, and spatial distribution. A composite TLS status score integrating these metrics was developed. Associations with pathological response, survival outcomes, and features of the tumor microenvironment (TME), including programmed death-ligand 1 (PD-L1) expression and immune cell composition were analyzed. Results:Greater TLS maturity was associated with earlier T-stage and clinical stages. Superior TLS characteristics-including advanced maturity, high density, large area, and stromal location-were significantly correlated with improved progression-free survival (PFS). Furthermore, patients who achieved a major pathological response (MPR) exhibited tumors characterized by more mature and denser TLS, and concomitant increase in tumor-infiltrating lymphocytes. A favorable TLS status, defined as a composite score =4, was a robust predictor of superior PFS [area under the curve (AUC) =0.82, P<0.001]. Furthermore, TLS maturity was inversely correlated with PD-L1 expression in the TME. Conclusions:TLS status, through its role in actively modulating the immune TME, serves as a predictive biomarker for neoadjuvant chemoimmunotherapy in resectable stage III NSCLC. This may offer a qualified advance for optimizing clinical therapeutics.

Background : Chemotherapy combined with immunotherapy (CIT) has reshaped the first-line treatment landscape for locally advanced and advanced non-small cell lung cancer (NSCLC). However, the optimal radiotherapy (RT) fractionation regimen for patients who remain inoperable after neoadjuvant therapy has yet to be defined. This study aimed to systematically compare survival outcomes and toxicity between hypofractionated radiotherapy (HFRT) and conventionally fractionated radiotherapy (CFRT) following induction CIT. Methods : In this retrospective analysis, 201 patients with locally advanced/advanced NSCLC receiving RT after CIT were divided into HFRT (45–54 Gy/15–18 fractions, n=69) and CFRT (60 Gy/30 fractions, n=132) groups. Overall survival (OS) was the primary endpoint; secondary endpoints included progression‑free survival (PFS), locoregional PFS (LPFS), and toxicity. Multivariable Cox regression and propensity score matching adjusted for confounders. A novel endpoint—LPFS based on conventional PTV—directly compared “gross‑tumor‑only” versus elective‑nodal irradiation. Results : After a median follow‑up of 26.2 months, adjusted analyses showed no significant differences in OS (HR=1.29, P=0.340), PFS, or LPFS between HFRT and CFRT. Exploratory analyses suggested trends favoring HFRT for PFS with consolidative immunotherapy (HR=0.58) and for OS/PFS in patients with high tumor burden (GTV ≥100 cm³; HR=0.85 and 0.88). HFRT was associated with significantly lower rates of acute radiation pneumonitis, key hematologic toxicities, and grade ≥2 pulmonary fibrosis (17.19% vs. 32.81%, P=0.041). The “PGTV‑only” strategy achieved locoregional control comparable to elective nodal irradiation (HR=1.063, P=0.765). All out‑of‑field nodal recurrences occurred with or after distant metastasis. Conclusion : HFRT provides survival outcomes equivalent to CFRT after CIT, with a more favorable safety profile, supporting a “precision intensification” paradigm of target‑volume de‑escalation combined with hypofractionation.

Aquaporin-4 (AQP4) is a biological macromolecules that primarily mediates water transport across biological membranes and, under specific conditions, may also permit the passage of certain reactive oxygen and nitrogen species (RONS), thereby contributing to the regulation of intracellular and extracellular redox balance. Recent studies have shown that therapeutic strategies involving oxidative stress are frequently accompanied by elevated RONS levels and lipid peroxidation of cellular membranes; however, how peroxidized lipid derivatives derived from POPC and POPE affect the structural properties of AQP4 and its associated transmembrane behavior remains poorly understood. In this study, we employed molecular dynamics simulations, free energy calculations, and computational electrophysiology to study the effects of different degrees of lipid peroxidation on AQP4-associated RONS transport behavior. Our results indicate that lipid peroxidation alters AQP4-lipid interactions and the local membrane microenvironment, thereby modulating the propensity of RONS molecules to access and traverse key regions of the AQP4 channel. These findings highlight the role of lipid-protein interactions under oxidative conditions in shaping channel associated transmembrane processes and provide a mechanistic framework for understanding redox-related transport phenomena.

Bulky solid tumors present significant therapeutic challenges. Spatially fractionated radiotherapy (SFRT), a technique delivering alternating high- and low-dose subvolumes, alters the tumor microenvironment while minimizing toxicity. This phase II trial assesses the efficacy and safety of SFRT combined with immune checkpoint inhibitors (ICIs) and anti-angiogenic agents in advanced malignancies. This prospective phase II trial enrolled 34 patients with bulky solid tumors between October 2024 and July 2025. All patients underwent SFRT using GRID, LATTICE, or Stereotactic central/core ablative radiation therapy techniques. Multimodal therapy, incorporating pre-radiotherapy administration of granulocyte-macrophage colony-stimulating factor and thymalfasin, as well as concurrent ICIs and anti-angiogenic agents during SFRT, was administered according to clinical recommendations and patient preferences. The endpoints were treatment-related adverse events and the objective response rate (ORR). In addition, a prognostic analysis was performed to identify factors associated with clinical outcomes. Among the 37 treatment courses in 34 patients, 4 patients did not complete the planned therapy, and 1 was lost to follow-up. The median follow-up duration was 6.0 months. Of the 32 evaluable lesions from patients who completed the study, the ORR was 65.63

Pharmacological targeting of ATR (ataxia telangiectasia and Rad3-related kinase), the master regulator of replication stress response, is emerging as a promising anticancer strategy. Despite the documented immune-modulatory effects of ATR inhibitors (ATRi), the immune evasion mechanisms constraining their therapeutic efficacy remain undefined. Here, we demonstrate that ATRi upregulates Galectin-9 (Gal-9), a ligand for the TIM-3 immune checkpoint, in tumor cells and host antigen-presenting cells (dendritic cells/macrophages) via STING-type I interferon (IFN-I) innate immune pathway. Notably, combining Gal-9 blockade with ATRi ceralasertib elicits potent anti-tumor effects and induces durable immunologic memory in syngeneic mouse models. In immune checkpoint-refractory lung cancer, the triple combination of ATRi, anti-Gal-9 and anti-PD-1 demonstrates superior efficacy. Mechanistically, Gal-9 blockade synergizes with ATRi to activate dendritic cells/macrophages and promote CD8+ T cell differentiation toward stem-like memory phenotypes with enhanced functional capacity. CD8+ T cell depletion completely abrogates the anti-tumor effects, suggesting their essential role in mediating therapeutic responses. These findings establish Gal-9 upregulation as a critical adaptive immune resistance mechanism constraining ATRi efficacy, providing a compelling rationale for clinical translation of ceralasertib/anti-Gal-9 combinations.

While radiotherapy (RT) is effective for local tumor control, it rarely induces the regression of non-irradiated metastases, a phenomenon known as the abscopal effect. The mechanisms constraining this systemic immune response remain poorly understood. This study investigates galectin-9 (Gal-9), a ligand for the TIM-3 (T-cell immunoglobulin and mucin-domain containing-3) immune checkpoint, as a mediator of immune escape that limits RT systemic efficacy and evaluates combinatorial RT/Gal-9 blockade in preclinical models. Background Methods Multiplatform analysis (RNA sequencing, immunoblot, flow cytometry, ELISA, immunohistochemistry) characterized RT-induced Gal-9 regulation in human lung/colorectal cancer cell lines, murine tumors/serums, and paired patient tumors. Local and abscopal therapeutic efficacy was evaluated in homologous (CT26/CT26, LLC/LLC) and heterologous (CT26/4T1) two-tumor mouse models. Immune profiling of tumor microenvironment, tumor-draining lymph nodes (tdLNs), and splenic compartments was comprehensively assessed by flow cytometry. Mechanistic studies employed STING (Stimulator of Interferon Genes) inhibition (H151), CD8 + T-cell depletion (anti-CD8α), macrophage/monocyte depletion (PLX-3397), interferon-I (IFN-I) blockade (anti-IFNAR1), and lymphocyte egress inhibition (FTY720). Results RT upregulated Gal-9 predominantly within host myeloid compartments (dendritic cells, macrophages, monocytes, neutrophils) versus tumor cells, in both irradiated tumors and abscopal tumors. Mechanistically, RT-activated STING-IFN-I axis locally induced Gal-9 + myeloid cells that subsequently disseminated systemically. Clinically, elevated post-RT Gal-9 in patient biopsies correlated with poor therapeutic outcomes. Notably, combining Gal-9 blockade with RT elicited potent abscopal responses in homologous two-tumor mouse models. Furthermore, anti-Gal-9 markedly enhanced radio-immunotherapy efficacy in the poorly immunogenic Lewis lung carcinoma. Immunologically, Gal-9 blockade synergized with RT to activate the myeloid and T cell compartments, enhancing dendritic cell accumulation in tdLNs and boosting CD8 + T cell infiltration in abscopal tumors. Depletion of CD8 + T cells/monocytes or blocking lymphocyte egress from lymph nodes abrogated the abscopal efficacy, underscoring their essential roles. Conclusions Our findings establish RT-induced Gal-9 as a novel dual myeloid/T-cell immune checkpoint restricting abscopal responses. Gal-9 blockade represents a promising strategy to potentiate radiotherapy against metastatic disease, defining a therapeutic paradigm distinct from conventional checkpoint inhibitors.

The study aimed to evaluate the safety and efficacy of simultaneous integrated dose reduction intensity-modulated radiotherapy (SIR-IMRT) in patients with locally advanced non-small-cell lung cancer (LA-NSCLC). In the SIR-IMRT conhort, the prescribed irradiation dose was 60 Gray (Gy) for the planning gross tumor volume (PGTV) and 54 Gy for the planning target volume (PTV), while in the conventional intensity-modulated radiotherapy (C-IMRT) cohort, it was 60 Gy for both PGTV and PTV. The SIR-IMRT group demonstrated better overall survival (OS) than the C-IMRT group, with a median OS of 37.7 versus 31.2 months. The SIR-IMRT group also experienced lower cardiac and esophagusal doses, along with a lower incidence of acute radiation esophagitis and ≥ grade 3 radiation pneumonitis. HeartV20 (the volume of the heart receiving at least 20 Gy) was the only independent risk factor associated with survival. SIR-IMRT significantly reduced cardiac irradiation exposure, improving patient survival and offering a new therapeutic direction for future studies.

Background:Limited-stage small-cell lung cancer (LS-SCLC) is highly aggressive and prone to brain metastasis (BM). Early identification of BM risk is crucial for devising personalized prophylactic cranial irradiation (PCI) strategies. This study aimed to develop a multimodal model integrating radiomic and clinical features to stratify BM risk in LS-SCLC patients and guide personalized PCI strategies. Methods:This study analyzed 141 LS-SCLC patients (2013-2021) using computed tomography (CT) images and clinical records. Patients were randomly divided into training (n=98), internal validation (n=43), and external validation cohorts (n=24). Radiomic features were extracted and optimized using the minimum redundancy maximum relevance (mRMR) algorithm to form a radiomic score (RadScore). Clinical predictors were identified via univariate logistic regression (LR). Four machine learning models-LR, support vector machine, random forest, and eXtreme Gradient Boosting-were used to develop predictive models. Model performance was evaluated by the area under the receiver operating characteristic curve (AUC). Results:A total of 141 patients (mean age, 59.03 years; 109 men and 32 women) were evaluated. A total of 1,037 radiomic features were extracted from the simulated positioning CT images, with 10 optimal features selected to form the RadScore. By incorporating dynamic changes in platelet count, hemoglobin levels, and leukocyte indices before and after radiotherapy, along with the baseline lymphocyte-to-monocyte ratio (LMR), the LR combined model demonstrated superior predictive capability. The LR combined model showed superior performance with AUCs of 0.831 (training), 0.831 (internal validation), and 0.863 (external validation). Risk stratification indicated that PCI reduced BM risk in high-risk patients [hazard ratio (HR) =0.270, P<0.001] but not in low-risk patients (HR =0.225, P=0.13). Conclusions:The LR combined radiomic-clinical model demonstrated superior predictive performance. PCI significantly reduced the risk of BM in high-risk patients, whereas no statistically significant benefit was observed in low-risk patients.

Background Despite the remarkable clinical outcomes of epidermal growth factor receptor (EGFR)-targeted therapies in patients with lung cancer, therapeutic resistance eventually develops. This study elucidates the role of galectin-9 (Gal-9), a TIM-3 immune checkpoint ligand, in facilitating tumor immune escape during EGFR tyrosine kinase inhibitor (TKI) therapy, and evaluates the therapeutic potential of combined EGFR-TKI and Gal-9 blockade in preclinical models.Methods EGFR-TKI-mediated Gal-9 regulation was systematically investigated through multianalysis including RNA-seq transcriptomics, quantitative reverse transcription-PCR, immunoblotting, ELISA, flow cytometry, and immunohistochemical validation across human and murine lung/colorectal cancer cell lines, murine tumor tissues, and paired patient tumor tissues/serum samples. Therapeutic efficacy was evaluated in two syngeneic murine models, with comprehensive immune monitoring of tumor microenvironment (TME), tumor-draining lymph nodes (tdLNs), and splenic compartments. Mechanistic investigations employed CD8+ T-cell/macrophage depletion strategies (anti-CD8α monoclonal antibodies (mAbs)/PLX-3397), type I interferon (IFN-I) pathway inhibition (anti-IFNAR1 mAbs), and lymph node retention approaches (FTY720 administration).Results EGFR-TKI treatment significantly induced Gal-9 expression in both tumor cells and host immune cells, particularly myeloid cells. Clinical validation revealed elevated Gal-9 levels in EGFR-TKI-treated patient with lung cancer tumor tissues and serums, correlating with reduced progression-free survival. Mechanistically, EGFR-TKIs triggered DNA damage-potentiated cytosolic double-stranded DNA accumulation and activated tumor-intrinsic STING-IFN-I innate immune pathway that transcriptionally regulated Gal-9 expression. Notably, Gal-9-neutralizing antibodies synergized with EGFR-TKI to markedly inhibit tumor growth in two syngeneic mouse models, including the poorly immunogenic LLC lung tumor model unresponsive to programmed cell death protein-1/programmed death-ligand 1 blockade. The combination therapy remodeled myeloid landscapes toward antigen-presenting phenotypes, promoted dendritic cell accumulation in the tdLN and enhanced CD8+ T response in the TME. Depleting CD8+ T cells or macrophages/monocytes abrogated the therapeutic benefits. Blocking the IFN-I pathway attenuated Gal-9 expression and enhanced the antitumor immunity of afatinib in the LLC tumor model.Conclusions These findings identify Gal-9 upregulation as a key mechanism mediating immune evasion and limiting EGFR-TKI efficacy, providing a promising combinational therapeutic strategy of EGFR-TKI and Gal-9 blockade for the treatment of EGFR-driven cancers.

BackgroundImmune checkpoint inhibitors (ICI) have revolutionized the therapeutic direction for lung cancer, yet their response rates remain unsatisfactory. Recently, the combination of ICI and low dose radiotherapy (LDR), a novel approach that effectively mobilizes innate and adaptive immunity, has gained interest among scientists. However, the underlying molecular mechanisms are not clearly elucidated.MethodsThe in vivo anti-tumor effects of LDR and ICI were measured in murine tumor models. The immune response and alterations in the tumor microenvironment were measured using flow cytometry and enzyme-linked immunosorbent assay (ELISA). Cell viability and death were assessed using CCK-8 assays. Fluorescent probes and ELISA were used to assess ferroptosis induced by the combination therapy in vitro and in vivo. Western blotting and qPCR were performed to detect alterations in the Nrf2/HO-1/GPX4 pathway. Furthermore, a phase 1 clinical trial with a combined regimen of LDR and anti-PD-1 antibodies in patients with lung cancer was conducted.ResultsThe combined LDR and ICI regimen exhibited considerable anti-tumor effects in murine tumor models, promoting immune response and increasing the IFN-γ levels. In vitro data showed that LDR plus ICI induced ferroptosis in cancer cells by increasing reactive oxygen species and MDA levels, promoting Fe2+ accumulation, and suppressing GSH. Furthermore, ferroptosis induced by combination therapy was associated with suppression of the Nrf2/HO-1/GPX4 antioxidant axis. Importantly, a phase 1 clinical trial of the combination therapy showed promising efficacy in patients with lung cancer with chemoimmunotherapy resistance.ConclusionThis study demonstrated that LDR plus ICI induces ferroptosis through the Nrf2/HO-1/GPX4 pathway, resulting in a significant anti-tumor effect and providing a combinatorial strategy to overcome lung cancer. However, this combined strategy merits further clinical investigation.

Background The prognosis of SCLC is poor and difficult to predict. The aim of this study was to explore whether a model based on radiomics and clinical features could predict the prognosis of patients with limited-stage small cell lung cancer (LS-SCLC). Methods Simulated positioning CT images and clinical features were retrospectively collected from 200 patients with histological diagnosis of LS-SCLC admitted between 2013 and 2021, which were randomly divided into the training ( n = 140) and testing ( n = 60) groups. Radiomics features were extracted from simulated positioning CT images, and the t-test and the least absolute shrinkage and selection operator (LASSO) were used to screen radiomics features. We then constructed radiomic score (RadScore) based on the filtered radiomics features. Clinical factors were analyzed using the Kaplan–Meier method. The Cox proportional hazards model was used for further analyses of possible prognostic features and clinical factors to build three models including a radiomic model, a clinical model, and a combined model including clinical factors and RadScore. When a model has prognostic predictive value (AUC > 0.7) in both train and test groups, a nomogram will be created. The performance of three models was evaluated using area under the receiver operating characteristic curve (AUC) and Kaplan–Meier analysis. Results A total of 1037 features were extracted from simulated positioning CT images which were contrast enhanced CT of the chest. The combined model showed the best prediction, with very poor AUC for the radiomic model and the clinical model. The combined model of OS included 4 clinical features and RadScore, with AUCs of 0.71 and 0.70 in the training and test groups. The combined model of PFS included 4 clinical features and RadScore, with AUCs of 0.72 and 0.71 in the training and test groups. T stages, ProGRP and smoke status were the independent variables for OS in the combined model, whereas T stages, ProGRP and prophylactic cranial irradiation (PCI) were the independent factors for PFS. There was a statistically significant difference between the low- and high-risk groups in the combined model of OS (training group, p < 0.0001; testing group, p = 0.0269) and PFS (training group, p < 0.0001; testing group, p < 0.0001). Conclusion Combined models involved RadScore and clinical factors can predict prognosis in LS-SCLC and show better performance than individual radiomics and clinical models.

Background The CREST study showed that the addition of thoracic radiotherapy (TRT) could improve the survival rate in patients with extensive stage small cell lung cancer (ES-SCLC), but whether TRT can bring survival benefit in the era of immunotherapy remains controversial. This study aimed to explore the efficacy and safety of adding TRT to the combination of PD-L1 inhibitors and chemotherapy. Methods The patients who received durvalumab or atezolizumab combined with chemotherapy as the first-line treatment of ES-SCLC from January 2019 to December 2021 were enrolled. They were divided into two groups, based on whether they received TRT or not. Propensity score matching (PSM) with a 1:1 ratio was performed. The primary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results A total of 211 patients with ES-SCLC were enrolled, of whom 70 (33.2%) patients received standard therapy plus TRT as first-line treatment, and 141 (66.8%) patients in the control group received PD-L1 inhibitors plus chemotherapy. After PSM, a total of 57 pairs of patients were enrolled in the analysis. In all patients, the median PFS (mPFS) in the TRT and non-TRT group was 9.5 and 7.2 months, respectively, with HR = 0.59 (95%CI 0.39–0.88, p = 0.009). The median OS (mOS) in the TRT group was also significantly longer than that in the non-TRT group (24.1 months vs. 18.5 months, HR = 0.53, 95%CI 0.31–0.89, p = 0.016). Multivariable analysis showed that baseline liver metastasis and the number of metastases ≥ 3 were independent prognostic factors for OS. Addition of TRT increased the incidence of treatment-related pneumonia ( p = 0.018), most of which were grade 1–2. Conclusions Addition of TRT to durvalumab or atezolizumab plus chemotherapy significantly improves survival in ES-SCLC. Although it may leads to increased incidence of treatment-related pneumonia, a majority of the cases can be relieved after symptomatic treatment.

Aquaporin 4 (AQP4) facilitates the transport of reactive oxygen species (ROS). Both cancer cells and the ionizing radiation microenvironment can induce posttranslational modifications (PTMs) in AQP4, which may affect its permeability to ROS. Because this ROS diffusion process is rapid, microscopic, and instantaneous within and outside cells, conventional experimental methods are inadequate for elucidating the molecular mechanisms involved. In this study, computational methods were employed to investigate the permeability of exogenous ROS mediated by radiation in AQP4 at a molecular scale. We constructed a simulation system incorporating AQP4 and AQP4-Cysp13 in a complex lipid environment with ROS. Long-timescale molecular dynamics simulations were conducted to assess the structural stability of both AQP4 and AQP4-Cysp13. Free energy calculations were utilized to determine the ROS transport capability of the two AQP4 proteins. Computational electrophysiology and channel structural analysis quantitatively evaluated changes in ROS transport capacity under various radiation-induced transmembrane voltage microenvironments. Our findings demonstrate the distinct transport capabilities of AQP4 channels for water molecules and various types of ROS and reveal a decrease in transport efficiency when AQP4 undergoes palmitoylation modification. In addition, we have simulated the radiation-induced alteration of cell membrane voltage, which significantly affected the ROS transport capacity. We propose that this research will enhance the understanding of the molecular mechanisms governing the transport of exogenous ROS by AQP4 and elucidate the influence of palmitoylation on ROS transport. This study will also help clarify how different structural features of AQP4 affect the transport of exogenous ROS mediated by radiotherapy, thereby providing a theoretical molecular basis for the development of new treatment strategies that combine with radiotherapy.

Although current cancer immunotherapies that target PD-1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor potential of T cells and benefit more patients. Galectin-9 (Gal-9), initially identified as a ligand for TIM-3 to induce T cell death, acts as an immunosuppressive regulator in the tumor microenvironment (TME) but its potential as a therapeutic target remains largely elusive. Here we show that antibody neutralization of Gal-9, in combination with inhibition of Ataxia telangiectasia mutated (ATM), a kinase essential for DNA damage response (DDR), is a promising modality for cancer immunotherapy. Genetic depletion of ATM in tumors markedly potentiated anti-Gal-9 therapy in a syngeneic mouse model. Mechanistically, ATM inhibition greatly upregulated Gal-9 expression and secretion in a variety of human and murine tumor cells via the cGAS-STING-interferon β (IFNβ) innate immune pathway. Combination of Gal-9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFNβ signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade.

目的:采用影像组学方法分析放疗定位CT影像的组学特点,构建预测局限期小细胞肺癌(limit-stage small cell lung cancer,LS-SCLC)患者总生存(overall survival,OS)期、无进展生存(progression-free survival,PFS)期的组学模型,为个体化治疗提供依据.方法:回顾性分析天津医科大学肿瘤医院2013年9月至2019年12月193例LS-SCLC患者的放疗定位CT资料,并将患者按照7:3分为训练组和测试组,勾画患者肿瘤区域(gross tumor volume,GTV)进行特征分析.随访获得的患者预后数据,以t检验和LASSO筛选特征建立随机森林预测模型,以曲线下面积(area under the receiver operating characteristic curve,AUC)对模型进行验证评估.结果:患者中位OS为29.77个月,中位PFS为19.03个月.每例患者提取了 1 037个影像特征,包含一阶特征、形状特征和纹理特征.分别以OS≤1年或OS≥3年、OS≤1年或OS≥5年、PFS≤6个月或PFS≥24个月作为标准对患者分组,各测试组模型的 AUC 均值分别为 0.73、0.79、0.70.组学特征中 original_ngtdm_Strength、wavelet-HHL_ngtdm_Busyness、wavelet-LLH_glcm_ClusterShade和wavelet-LLH_glcm_Correlation等参数具有预测价值.结论:基于放疗定位CT的影像组学获得的影像特征模型对LS-SCLC患者预后有一定预测价值,纳入临床因素建立融合模型综合分析可能获得更为理想的结果.

Objective:To investigate the radiation dose and fractionation regimens for limited stage small cell lung cancer (LS-SCLC) in Chinese radiation oncologists.Methods:Over 500 radiation oncologists were surveyed through questionnaire for radiation dose and fractionation regimens for LS-SCLC and 216 valid samples were collected for further analysis. All data were collected by online questionnaire designed by WJX software. Data collection and statistical analysis were performed by SPSS 25.0 statistical software. The differences in categorical variables among different groups were analyzed by Chi-square test and Fisher's exact test. Results:Among 216 participants, 94.9% preferred early concurrent chemoradiotherapy, 69.4% recommended conventional fractionation, 70.8% preferred a total dose of 60 Gy when delivering conventional radiotherapy and 78.7% recommended 45 Gy when administering hyperfractionated radiotherapy.Conclusions:Despite differences in LS-SCLC treatment plans, most of Chinese radiation oncologists prefer to choose 60 Gy conventional fractionated radiotherapy as the main treatment strategy for LS-SCLC patients. Chinese Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN) and Chinese Medical Association guidelines or expert consensus play a critical role in guiding treatment decision-making.

PDF File - 501K, PF02341066 is well tolerated in female athymic nude mice.

Immunotherapies that block PD-L1/PD-1 immune checkpoint proteins represent a landmark breakthrough in cancer treatment. Although the role of PD-L1 in suppressing T cell activity has been extensively studied, its cancer cell-intrinsic functions are not well understood. Herein, we demonstrated that PD-L1 is important for the repair of DNA damage in cancer cells. Mechanically, depletion of PD-L1 led to the downregulation of the critical molecules involved in the homologous recombination (HR) repair pathway, such as ATM and BRCA1, but did not obviously affect the non-homologous end joining (NHEJ) pathway. Notably, PD-L1 silence sensitized cancer cells to chemotherapy agents and the inhibitor of DNA-PK, which is an important kinase for NHEJ. Furthermore, PD-L1 depletion potentiated DNA damage-induced cGAS-STING pathway and induction of IFNβ. The regulation of DNA repair and cGAS-STING pathway by PD-L1 represents its connection with innate immunity that can be exploited to enhance the efficacy of existing immunotherapy. Our findings thus expand the focus of PD-L1 from tumor antigen-specific CD8+ T cells to innate immunity, and support targeting tumor-intrinsic PD-L1 combined with DNA-PK inhibition for tumor eradication, through promoting synthetic lethality and innate immune response.

Objective:To investigate the effect of low-dose ionizing radiation on blood cell parameters of radiation workers.Methods:A total of 124 staff members engaged in radiology were selected into the observation group, and they were divided into 4 subgroups of physicians, physicists, technicians, and maintainer according to their jobs. A total of 130 non-radiation-related staff members from the same hospital were selected into the control group. Blood cell parameters of peripheral blood of all subjects from 2016 to 2019 were collected, and the differences in blood cell parameters between the radiation group and the control group as well as 4 subgroups of the control group were analyzed and compared, and the correlation between the differences in blood cell parameters and the cumulative radiation dose was compared.Results:Compared with the control group, the white blood cell count, neutrophil count, red blood cell count and hemoglobin count in the observation group were lower than those in the control group (all P<0.05). There are no significant differences in cumulative radiation dose among different types of work (all P>0.05). Correlation analysis showed that the blood cell parameters of peripheral blood cells were not significantly correlated with the cumulative radiation dose. The blood cell count changes after 4-year low-dose ionizing radiation between the physicist group, the technician group and the maintainer sub-group were significantly different (all P<0.05), but the above differences were not related to the cumulative radiation dose (all P>0.05). Conclusions:Under the same exposure and protection conditions, the blood cell counts of different radiation-related workers are not significantly different, and the long-term cumulative radiation dose has no significant correlation with blood cell parameters. Therefore, peripheral blood cell parameters can no longer be used as a good indicator to reflect radiation damage, and it is urgent to find more convenient, intuitive and sensitive indicators of radiation damage.