First-line treatment of driver gene-negative metastatic lung adenocarcinoma with malignant pleural effusion: Should chemotherapy be combined with an immune checkpoint inhibitor or bevacizumab?

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.

Chemoimmunotherapy combined with consolidative thoracic radiotherapy for extensive-stage small cell lung cancer: A systematic review and meta-analysis.

INTRODUCTION: This study aimed to evaluate the efficacy and safety of chemoimmunotherapy combined with consolidative thoracic radiation therapy (cTRT) in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A meta-analysis was conducted. PubMed, Embase, Web of Science, and the Cochrane Library were searched. The study was registered in PROSPERO (registration no. CRD42023410344). RESULTS: A total of 4677 studies were initially screened and 15 studies encompassing a total of 1033 patients were included. Chemoimmunotherapy combined with cTRT significantly improved survival (HR = 0.52, 95 % CI: 0.39, 0.68) with favorable 6-month (0.89, 95 % CI: 0.77, 1.00) and 1-year (0.77, 95 % CI: 0.72, 0.82) OS, without affecting ≥3 grade TRAEs (RR = 1.29, 95 % CI: 0.85, 1.98). Pooled 6-month and 1-year PFS were 0.67 (95 % CI: 0.47, 0.86) and 0.38 (95 % CI: 0.22, 0.55), respectively. Incidence of ≥3 grade TRAEs was 0.24 (95 % CI: 0.08, 0.39) and radiation pneumonitis was 0.03 (95 % CI: 0.01, 0.06). CONCLUSIONS: Chemoimmunotherapy combined with cTRT improves survival and shows favorable outcomes in ES-SCLC patients, with manageable adverse events. Further research with larger samples is needed to confirm these findings.

Cranial radiation therapy with hippocampus avoidance in lung cancer treatment: systematic review and meta-analysis.

Background: The role of cranial radiation therapy with hippocampus avoidance (HA-CRT) in neurocognitive function (NCF), brain metastasis (BM), and overall survival (OS) in lung cancer remains unclear. Methods: A meta-analysis was conducted to evaluate the impact of HA-CRT in lung cancer. Data from studies on hippocampal-avoidance prophylactic cranial irradiation (HA-PCI) and whole brain radiotherapy (HA-WBRT) were pooled. Results: A total of 14 studies, including 5 randomized controlled trials, were included. The focus of NCF was mainly via the Hopkins Verbal Learning Test-Revised or the Free and Cued Selective Reminding Test. At 6 months post-radiotherapy, the pooled proportion of participants with decline in the performance of total recall, delayed recall, and discrimination in neurocognitive tests were 0.22 (95% CI 0.15, 0.29), 0.20 (95% CI 0.13, 0.27), and 0.14 (95% CI 0.05, 0.24) respectively. After 12 months, the proportion were 0.16 (95% CI 0.08, 0.23), 0.10 (95% CI 0.04, 0.16), and 0.04 (95% CI 0, 0.09) respectively. For HA zone relapse, the RR of HA-CRT versus CRT was 2.72 (95% CI 0.53, 13.87), and for 2-year BM, it was 1.20 (95% CI 0.82, 1.75). Regarding HA-PCI in SCLC, the 1-year BM rate was 0.12 (95% CI 0.07, 0.17), and the 2-year BM rate was 0.20 (95% CI 0.16, 0.25). For HA-WBRT in NSCLC with BM, the 2-year intracranial progression rate was 0.38 (95% CI 0.13, 0.62). There was no significant difference in OS between HA-CRT and CRT. Conclusions: HA-CRT appears to be safe in lung cancer, but it may not outperform conventional CRT. Larger RCTs comparing HA-CRT and CRT are warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022360890, identifier CRD42022360890.

Diverse regulated cell death modes predict the immune microenvironment and drug sensitivity in lung adenocarcinoma.

Integrated action modes of regulated cell death (RCD) in lung adenocarcinoma (LUAD) have not been comprehensively dissected. Here, we adopted 15 RCD modes, including 1350 related genes, and established RCD signature scores. We found that LUAD patients with high RCD scores had a significantly worse prognosis in all four different cohorts (TCGA, KM-plotter, GSE31210, and GSE30219). Our nomogram established based on the RCD score and clinical characteristics performed well in both the discovery and validation sets. There was a close correlation between the RCD scores and LUAD molecular subtypes identified by unsupervised consensus clustering. Furthermore, we profiled the tumor microenvironment via deconvolution and found significant differences in immune activity, transcription factor activity and molecular pathway enrichment between the RCD-high and RCD-low groups. More importantly, we revealed that the regulation of antigen presentation is the crucial mechanism underlying RCD. In addition, higher RCD scores predict poorer sensitivity to multiple therapeutic drugs, which indicates that RCD scores may serve as a promising predictor of chemotherapy and immunotherapy outcomes. In summary, this work is the first to reveal the internal links between RCD modes, LUAD, and cancer immunity and highlights the necessity of RCD scores in personalizing treatment plans.

Involved-field irradiation or elective-nodal irradiation in neoadjuvant chemo-radiotherapy for locally-advanced esophageal cancer: comprehensive analysis for dosimetry, treatment-related complications, impact on lymphocyte, patterns of failure and survival.

Purpose: To compare the differences between involved-field irradiation (IFI) and elective nodal irradiation (ENI) in selecting the optimal target area for neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). Materials and methods: We retrospectively analyzed 267 patients with LA-ESCC, of whom 165 underwent ENI and 102 underwent IFI. Dosimetry, treatment-related complications, pathological responses, recurrence/metastasis patterns, and survival were compared between the two groups. Results: The median follow-up duration was 27.9 months. The R0 resection rates in the IFI and ENI groups were 95.1% and 92.7%, respectively (p=0.441), while the pathological complete response (pCR) rates were 42.2% and 34.5%, respectively (p=0.12). The ENI group received higher radiation doses to the heart (HV30:23.9% vs. 18%, p=0.033) and lungs (LV30:7.7% vs. 4.9%, p<0.001) than the IFI group. Consequently, the ENI group showed a higher incidence of grade 2 or higher radiation pneumonitis (30.3% vs. 17.6%, p=0.004) and pericardial effusion (26.7% vs. 11.8%, p=0.021) than the IFI group. Post-operation fistulas were observed in 3 (2.9%) and 17 cases (10.3%) in the IFI and ENI groups, respectively (p=0.026). In the multivariate analysis, smoking, positive lymph node involvement (pN+), and anastomotic fistula were independent predictors of overall survival (OS). The pN+ patients exhibited a greater propensity for recurrence compared to pN- patients, especially in the first year of follow-up (6.67% vs. 0.56%, p=0.003). Conclusion: The ENI group had a higher incidence of radiation-induced adverse events compared to the IFI group, likely due to the higher radiation doses to normal tissues. Considering the similar disease-free survival (DFS) and OS rates in the two groups, IFI may be suitable for nCRT in patients with LA-ESCC, although further prospective studies are warranted.

Safety and Tolerability of Low-Dose Radiation and Stereotactic Body Radiotherapy + Sintilimab for Treatment-Naïve Stage IV PD-L1+ Non-Small Cell Lung Cancer Patients.

PURPOSE: Low-dose radiotherapy (LDRT) may enhance the synergistic antitumor effect of combined immunotherapy and stereotactic body radiotherapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This prospective phase I study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT [30 Gray (Gy)/3f] to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a programmed death-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAE) occurred in 96.6% (28/29) of patients [grade ≥ 3; 20.7% (6/29)]; 2 patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval, 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging T-cell receptor clonotypes were associated with better PFS. CONCLUSIONS: The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with programmed death ligand-1-positive, driver gene-negative primary metastatic NSCLC.

A New Type of Endometrial Cancer Models in Mice Revealing the Functional Roles of Genetic Drivers and Exploring their Susceptibilities.

Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing-based strategy to generate primary, orthotopic, and driver-defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid-initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high-throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Immunogenetic polymorphisms predict therapeutic efficacy and survival outcomes in tumor patients receiving PD-1/PD-L1 blockade.

BACKGROUND: While immune checkpoint inhibitors (ICIs) demonstrate remarkable clinical responses, only a small subset of patients obtains benefits. Genes linked to the tumor immune system are confirmed to be critical for the treatment of ICIs, and their polymorphisms can contribute to ICI efficacy. Here, we examined the potential of immunogenetic variations to predict the efficacy and survival of the PD-1/PD-L1 blockade. METHODS: Cancerous patients receiving PD-1/PD-L1 blockade were recruited and followed up. Pivotal genes related to tumor-immunity were filtered through a protein-protein interaction network and the degree algorithm in Cytoscape. Finally, 39 genetic variants were genotyped through multiplex genotyping assays. Association analyses between variants and ICI efficacy and progression-free survival (PFS) were performed. RESULTS: Overall, 318 patients were ultimately enrolled. Hence, three immunogenetic variants were identified as predictors of PD-1/PD-L1 blockade response. Mutant alleles from ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911 were all at increased risk of tumor progression following ICI therapy (OR: 1.475, 1.641, 1.462, respectively; P value: 0.028, 0.017, 0.027, respectively). Significant immunogenetic variants also attained similar trends in the PD-1 blockade, lung cancer, or lung cancer using PD-1 blockade subgroups. Furthermore, the mutant genotypes of CD274 rs2297136 (GG as the reference: HR: 0.50 (95%CI: 0.29-0.88), P value: 0.015) and TLR4 rs1927911 (AA as the reference: HR: 0.65 (95%CI: 0.47-0.91), P value: 0.012) indicated poorer PFS and were both independent prognostic factors. CONCLUSION: Immunogenetic polymorphisms, including ATG7 rs7625881, CD274 rs2297136, and TLR4 rs1927911, were first identified as potential predictors of response to PD-1/PD-L1 blockade in tumor patients.

Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

Background: The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application. Objective: This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs. Methods: We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted. Results: In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00-1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65-5.11), ipilimumab (OR: 2.66, 95% CI: 1.42-4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40-4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88-2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90-3.57), fluindione (OR: 6.48, 95% CI: 2.72-15.46), diuretic (OR: 1.78, 95% CI: 1.32-2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15-2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study. Conclusion: The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

DNMT3AR882H accelerates angioimmunoblastic T-cell lymphoma in mice.

DNA methylation-related genes, including TET2, IDH2, and DNMT3A are highly frequently mutated in angioimmunoblastic T-cell lymphoma (AITL), an aggressive malignancy of T follicular helper (Tfh) cells associated with aberrant immune features. It has been shown that TET2 loss cooperates with RHOAG17V to promote AITL in mice but the functional role of DNMT3A mutations in AITL remains unclear. Here, we report that DNMT3AR882H, the most common mutation of DNMT3A in AITL, accelerates the development of Tet2-/-; RHOAG17V AITL in mice, indicated by the expansion of malignant Tfh cells and aberrant B cells, skin rash, and significantly shortened disease-free survival. To understand the underlying cellular and molecular mechanisms, we performed single-cell transcriptome analyses of lymph nodes of mice transplanted with Tet2-/-, Tet2-/-; RHOAG17V or DNMT3AR882H; Tet2-/-; RHOAG17V hematopoietic stem and progenitor cells. These single-cell landscapes reveal that DNMT3A mutation further activates Tfh cells and leads to rapid and terminal differentiation of B cells, probably through enhancing the interacting PD1/PD-L1, ICOS/ICOSL, CD28/CD86, and ICAM1/ITGAL pairs. Our study establishes the functional roles of DNMT3A mutation in AITL and sheds light on the molecular mechanisms of this disease.

Optimal timing of hypofractionated stereotactic radiotherapy for epidermal growth factor receptor-mutated non-small-cell lung cancer patients with brain metastases.

BACKGROUND: For epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients with limited brain metastases (BMs), who eventually receive both tyrosine kinase inhibitors (TKIs) treatment and brain radiotherapy, the optimal timing of radiotherapy is not clear. The present retrospective analysis aimed to partly solve this problem. METHODS: In total 84 EGFR-mutated NSCLC patients with limited BMs, who received both TKI treatment and brain hypofractionated stereotactic radiotherapy (HSRT), were enrolled. Patients were divided into three groups based on whether the HSRT was administrated 2 weeks before or after the beginning of TKI treatment (upfront HSRT), when intracranial lesions stabilized after TKI treatment (consolidative HSRT), or when the intracranial disease progressed after TKI treatment (salvage HSRT). The clinical efficacy and toxicities were evaluated. RESULTS: The median intracranial progression-free survival (iPFS) and overall PFS calculated from the initiation of HSRT (iPFS1 and PFS1) of all patients were 17.5 and 13.1 months, respectively. The median iPFS and PFS calculated from the initiation of TKI treatment (iPFS2 and PFS2) of all patients were 24.1 and 18.4 months, respectively. Compared to consolidative and salvage HSRT, upfront HSRT improved iPFS1 (not reached vs. 17.5 months vs. 11.0 months, p < 0.001) and PFS1 (18.4 months vs. 9.1 months vs. 7.9 months, p < 0.001), and reduced the initial intracranial failure rate (12.5% vs. 48.1% vs. 56%, p < 0.001). However, there were no significant differences between the three groups for iPFS2, PFS2, and overall survival. Hepatic metastases and diagnosis-specific Graded Prognostic Assessment (ds-GPA) at 2-3 were poor prognostic factors. CONCLUSION: For patients who receive both TKI treatment and brain HSRT, the timing of HSRT does not seem to influence the eventual therapeutic effect. Further validation in prospective clinical studies is needed.

Immunogenetic variations predict immune-related adverse events for PD-1/PD-L1 inhibitors.

BACKGROUND: PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs. METHODS: Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein-protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed. RESULTS: Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093-2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521-0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355-4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205-0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52-0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025-0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315-7.29, P = 0.01) were independent variables for high-grade irAEs-free survival. CONCLUSION: We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers.

Organoid technology and applications in lung diseases: Models, mechanism research and therapy opportunities.

The prevalency of lung disease has increased worldwide, especially in the aging population. It is essential to develop novel disease models, that are superior to traditional models. Organoids are three-dimensional (3D) in vitro structures that produce from self-organizing and differentiating stem cells, including pluripotent stem cells (PSCs) or adult stem cells (ASCs). They can recapitulate the in vivo cellular heterogeneity, genetic characteristics, structure, and functionality of original tissues. Drug responses of patient-derived organoids (PDOs) are consistent with that of patients, and show correlations with genetic alterations. Thus, organoids have proven to be valuable in studying the biology of disease, testing preclinical drugs and developing novel therapies. In recent years, organoids have been successfully applied in studies of a variety of lung diseases, such as lung cancer, influenza, cystic fibrosis, idiopathic pulmonary fibrosis, and the recent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. In this review, we provide an update on the generation of organoid models for these diseases and their applications in basic and translational research, highlighting these signs of progress in pathogenesis study, drug screening, personalized medicine and immunotherapy. We also discuss the current limitations and future perspectives in organoid models of lung diseases.

Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer.

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.

Novel directions of precision oncology: circulating microbial DNA emerging in cancer-microbiome areas.

Microbiome research has extended into the cancer area in the past decades. Microbes can affect oncogenesis, progression, and treatment response through various mechanisms, including direct regulation and indirect impacts. Microbiota-associated detection methods and agents have been developed to facilitate cancer diagnosis and therapy. Additionally, the cancer microbiome has recently been redefined. The identification of intra-tumoral microbes and cancer-related circulating microbial DNA (cmDNA) has promoted novel research in the cancer-microbiome area. In this review, we define the human system of commensal microbes and the cancer microbiome from a brand-new perspective and emphasize the potential value of cmDNA as a promising biomarker in cancer liquid biopsy. We outline all existing studies on the relationship between cmDNA and cancer and the outlook for potential preclinical and clinical applications of cmDNA in cancer precision medicine, as well as critical problems to be overcome in this burgeoning field.

HIF-1-dependent heme synthesis promotes gemcitabine resistance in human non-small cell lung cancers via enhanced ABCB6 expression.

Gemcitabine is commonly used to treat various cancer types, including human non-small cell lung cancer (NSCLC). However, even cases that initially respond rapidly commonly develop acquired resistance, limiting our ability to effectively treat advanced NSCLC. To gain insight for developing a strategy to overcome gemcitabine resistance, the present study investigated the mechanism of gemcitabine resistance in NSCLC according to the involvement of ATP-binding cassette subfamily B member 6 (ABCB6) and heme biosynthesis. First, an analysis of ABCB6 expression in human NSCLCs was found to be associated with poor prognosis and gemcitabine resistance in a hypoxia-inducible factor (HIF)-1-dependent manner. Further experiments showed that activation of HIF-1α/ABCB6 signaling led to intracellular heme metabolic reprogramming and a corresponding increase in heme biosynthesis to enhance the activation and accumulation of catalase. Increased catalase levels diminished the effective levels of reactive oxygen species, thereby promoting gemcitabine-based resistance. In a mouse NSCLC model, inhibition of HIF-1α or ABCB6, in combination with gemcitabine, strongly restrained tumor proliferation, increased tumor cell apoptosis, and prolonged animal survival. These results suggest that, in combination with gemcitabine-based chemotherapy, targeting HIF-1α/ABCB6 signaling could result in enhanced tumor chemosensitivity and, thus, may improve outcomes in NSCLC patients.

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming.

Small cell lung cancer (SCLC) is notorious for its early and frequent metastases, which contribute to it as a recalcitrant malignancy. To understand the molecular mechanisms underlying SCLC metastasis, we generated SCLC mouse models with orthotopically transplanted genome-edited lung organoids and performed multiomics analyses. We found that a deficiency of KMT2C, a histone H3 lysine 4 methyltransferase frequently mutated in extensive-stage SCLC, promoted multiple-organ metastases in mice. Metastatic and KMT2C-deficient SCLC displayed both histone and DNA hypomethylation. Mechanistically, KMT2C directly regulated the expression of DNMT3A, a de novo DNA methyltransferase, through histone methylation. Forced DNMT3A expression restrained metastasis of KMT2C-deficient SCLC through repressing metastasis-promoting MEIS/HOX genes. Further, S-(5'-adenosyl)-L-methionine, the common cofactor of histone and DNA methyltransferases, inhibited SCLC metastasis. Thus, our study revealed a concerted epigenetic reprogramming of KMT2C- and DNMT3A-mediated histone and DNA hypomethylation underlying SCLC metastasis, which suggested a potential epigenetic therapeutic vulnerability.

Identifying a confused cell identity for esophageal squamous cell carcinoma.

The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer. Here, we report that esophageal squamous cell carcinoma (ESCC) cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells, which we term as confused cell identity (CCI). CCI is an independent prognostic marker associated with poor prognosis in ESCC. Further, we identify tropomyosin 4 (TPM4) as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo. And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway. Thus, our study suggests an unrecognized feature of ESCC cells, which might be of value for clinic prognosis and potential interference.

Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine.

Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-ß pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8+ T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.

An organoid-based drug screening identified a menin-MLL inhibitor for endometrial cancer through regulating the HIF pathway.

Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery. Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors. Among them, menin-MLL inhibitors MI-136 and MI-463 scored. The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo. CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136. Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment. Consistently, Men1, Kmt2a, and Ash2l knockout also repressed the expressions of the HIF target genes. Loss of Hif1a or Hif1b partially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth. Further, we found that MEN1 was upregulated in human endometrial cancers, which were tightly correlated with the expression levels of HIF1A, and associated with poor prognosis. Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients. Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer.