Cancer Science最新文献

We investigated immunologic biomarkers that predict outcomes of patients with previously treated metastatic non-small cell lung cancer who were enrolled in the J-TAIL study, a prospective, observational study of atezolizumab monotherapy. Of 262 patients participating in the J-TAIL exploratory study, peripheral blood mononuclear cells were obtained from 51 patients and analyzed by T-cell fractionation analysis using Helios mass cytometry and serum proteomics analysis. Following treatment with atezolizumab, an increase in programmed cell death-1 (PD-1)-expressing CD8 and CD4 T-cell populations was observed. A more pronounced increase in PD-1 expression was seen in T cells from patients whose progression-free survival (PFS) was 100 days or longer compared with those with shorter PFS. The proximity extension assay, which is highly sensitive multiplex analysis technology that combines antibody-based affinity assays with next-generation sequencing, showed a significant increase in FOXO1, possibly in response to precursor-exhausted T-cell population activation. Immune-related adverse events were associated with a high percentage of PD-1-positive cells on effector memory CD8 T cells, which was thought to be accompanied by extremely high CD8 T-cell activation. Further analysis distinguished poor prognosis populations with significant differences in CD62L_high Th7R and CXCR3⁺ component of Th7R (CXCR3⁺ Th7R) within the population with PFS < 50 days. Patients with low Th7R or CXCR3⁺ Th7R percentages prior to atezolizumab treatment had significantly poorer overall survival. These findings provide valuable insights regarding T-cell kinetics and biomarkers in atezolizumab therapy and may offer promising directions for future research. Trial Registration: UMIN Clinical Trials Registry: UMIN000033133 and UMIN000035567; ClinicalTrials.gov: NCT03645330.

Hepatocellular carcinoma (HCC) has a poor prognosis and high mortality. Ferroptosis, an iron-dependent regulated cell death process, is implicated in cancer development and treatment. Wnt signaling and lysyl oxidase (Lox) family members are associated with ferroptosis. This study investigates how Wnt3a and/or Loxl2 knockdown affects liver cancer stem cells (LCSCs) and orthotopic tumor growth in mice, and explores the role of ferroptosis-related genes. Bioinformatics identified ferroptosis- and HCC-associated differentially expressed genes (DEGs) correlated with Wnt3a/Loxl2. LCSCs sorted from Hep3B were transduced with lentivirus for gene knockdown. Ferroptosis markers and DEG expression were analyzed. Wnt3a/Loxl2 knockout mice were generated using CRISPR-Cas9, and orthotopic tumor models were established. Tumor inhibition rates, ferroptosis-related indicators, and DEG expression were assessed. 199 ferroptosis-related DEGs were identified in HCC; ZEB1 was selected as a key gene via PPI analysis. Wnt3a/Loxl2 knockdown increased Fe²⁺ and MDA, and decreased GSH, most evidently in double-knockdown cells. In vivo, single- and double-knockout groups showed suppressed tumor growth, with inhibition rates of 51%, 71%, and 93%, respectively. Tumor tissues exhibited similar ferroptosis marker changes. ZEB1 was upregulated in both cellular and animal knockout models. Wnt3a/Loxl2 knockdown promotes ferroptosis in LCSCs and inhibits orthotopic tumor growth, with the strongest effect following dual-gene knockout. ZEB1 may be an important regulatory factor in this process.

Tumor mutational burden (TMB) is a key biomarker for predicting the response to immune checkpoint inhibitors (ICIs). However, its predictive accuracy in real-world clinical practice, particularly in Asian populations, remains inadequately evaluated. We addressed this issue by analyzing real-world data from 63,952 patients registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, which integrates genomic and clinical information from Japanese patients with various advanced solid tumors. We assessed the therapeutic efficacy of pembrolizumab in 1899 patients who underwent one of three comprehensive genomic profiling tests: FoundationOne CDx, the OncoGuide NCC Oncopanel System, or the GenMine TOP Cancer Genome Profiling System. Based on the reported TMB values, patients were classified as TMB-high (≥ 10 mutations per megabase) or TMB-low (< 10 mutations per megabase). The objective response rate (ORR) among 946 TMB-high patients exceeded 30% and was significantly higher than that observed in 953 TMB-low patients (16.8%, p < 0.001). Notably, patients with borderline TMB values (10 to less than 13 mutations per megabase) exhibited relatively modest responses (20.8%). The ORR improved when hotspot mutations were excluded from the TMB calculation, suggesting that this adjustment enhances the predictive accuracy of TMB. These findings support the clinical utility of TMB as a biomarker for predicting ICI response in routine oncology practice. In particular, excluding hotspot mutations from TMB calculations may improve response prediction in patients whose TMB values are near the threshold.

Ramucirumab plus docetaxel (RAM+DOC) demonstrates clinical activity after programmed cell death-1 (PD-1) inhibitors in advanced non-small cell lung cancer (NSCLC); however, the underlying mechanisms remain unclear. We aimed to evaluate clinical efficacy and explore immunologic dynamics and benefit-associated biomarkers. Patients treated with RAM+DOC after PD-1 inhibitors were enrolled in a multicenter prospective cohort. Anti-PD-1 antibody bound (IgG4⁺) T-cell subsets were measured at baseline (T0) and after 2-3 cycles (T1), reflecting residual anti-PD-1 antibody binding on circulating T cells. T1/T0 ratios of immune subsets were calculated to assess dynamics. Landmark analyses at T1 evaluated associations with progression-free survival (PFS) and overall survival (OS). Prognostic biomarkers were assessed at baseline. Among 27 evaluable patients, the objective response rate was 37.0%, median PFS 5.1 months, and OS 10.4 months. RAM + DOC responders had higher IgG4⁺CD8⁺ T-cell and lower IgG4⁺ Treg T1/T0 ratios (both p < 0.001). Higher IgG4⁺CD8⁺ ratios were associated with longer landmark PFS (p = 0.002) and OS (p = 0.016) and were inversely correlated with IgG4⁺ Treg ratios (p = 0.008). Among the baseline factors, high IgG4⁺CD8⁺ Temra conferred survival benefits (OS, not reached vs. 8.2 months; p = 0.006), and low vascular endothelial growth factor (VEGF)-C levels were associated with longer OS (not reached vs. 8.5 months, p = 0.044). Both variables remained independent prognostic factors of PFS and OS in multivariable analysis. Our findings suggest that sequential strategy administering RAM+DOC during persistent binding of anti-PD-1 antibody to T cells may be beneficial. IgG4⁺CD8⁺ Temra and VEGF-C levels at RAM+DOC initiation may serve as biomarkers of survival benefit. Trial Registration: UMIN-Clinical Trials Registry (UMIN000050478).

In the Phase III TASUKI-52 trial, nivolumab with carboplatin, paclitaxel (CP), plus bevacizumab significantly prolonged progression-free survival (PFS), and resulted in longer overall survival (OS) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). This final analysis evaluated 4-year treatment outcomes in terms of OS, PFS and duration of response (DOR) by investigator assessment and safety, as well as the background characteristics and treatment courses associated with 4-year survivors. Patients were randomized 1:1 to receive nivolumab (n = 275) or placebo (n = 275) in addition to CP plus bevacizumab. With a minimum follow-up of 53.1 months, nivolumab with CP plus bevacizumab continued to show improvement in OS (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.88) and PFS (HR: 0.61; 95% CI: 0.50-0.74) compared to placebo with CP plus bevacizumab. The 4-year OS rate was 34.7% in the nivolumab arm versus 22.1% in the placebo arm, and the 4-year PFS rate was 13.7% in the nivolumab arm versus 3.3% in the placebo arm. Among 4-year survivors, the median DOR was numerically longer in the nivolumab arm than in the placebo arm (34.7 vs. 13.5 months). No new safety signals were observed. Four-year survival in the nivolumab arm was associated with the absence of bone metastases and age < 65, but not with PD-L1 status and tumor size. In conclusion, treatment with nivolumab demonstrated long-term survival benefit and durable response, which supports nivolumab with CP plus bevacizumab as a first-line treatment option for advanced nonsquamous NSCLC. Trial Registration: ClinicalTrials.gov identifier: NCT03117049.

Therapy-induced senescence (TIS) is a state in which cancer cells enter growth arrest following chemotherapy. TIS cancer cells influence the tumor microenvironment through their senescence-associated secretory phenotype and independently acquire stem-like properties, both of which contribute to increased aggressiveness and tumor relapse. Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. This elimination occurred via apoptosis associated with caspase 8 activation. These TIS cancer cells produced and secreted tumor necrosis factor α (TNFα); however, the selective cytotoxicity of IAP antagonists toward TIS cells was unexpectedly largely TNFα-independent. Consistently, the same IAP antagonists sensitized cancer cells treated with nutlin-3a, which induces senescence without TNFα production. Depletion of both cIAP1 and XIAP recapitulated the selective cytotoxicity against both TIS and nutlin-3a-induced senescent cancer cells. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells.

TIF1β/TRIM28/KAP1 has been recognized as a scaffold protein that partners with KRAB-ZFPs and heterochromatin complexes to enforce gene silencing. In embryonic and pluripotent stem cells, it maintains self-renewal by silencing endogenous retroelements through the establishment of heterochromatin. While these canonical functions have been extensively examined in embryonic stem (ES) cells, accumulating evidence also highlights its diverse contributions to cancer biology. We herein focused on the oncogenic role of TIF1β in leukemic progression, contrasting this with its physiological roles in hematopoietic stem cell maintenance, differentiation, and immune regulation, thereby providing a comparative perspective on H3K9 methyltransferase SETDB1-dependent and -independent mechanisms. TIF1β-mediated epigenetic plasticity was recently shown to establish a leukemic chromatin environment for promoting oncogenic transcriptional programs while repressing lineage-differentiation regulators, which drives leukemic progression in a context-dependent manner. This review summarizes the dual role of TIF1β as a chromatin modulator, functioning both as a canonical transcriptional co-repressor and as a context-dependent co-activator, and also discusses how these modalities cooperate to sustain leukemic stem cell programs.

While baseline body mass index (BMI) has been inversely associated with lung cancer risk, the impact of BMI change remains unclear. Furthermore, stratified analysis by menopausal status and age has not been explored. Cancer-free participants who completed National Health Examinations in 2010 and again in 2014 were included (n = 3,822,171; follow-up through 2021). BMI was measured at both time points, and changes were categorized. We modeled competing-risk outcomes using the Fine-Gray approach to obtain adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CI). During follow-up, 43,704 lung cancer cases occurred. Persistent obesity (obesity I [25.0-29.9 kg/m²], aHR 0.93, 95% CI 0.89-0.97; persistent obesity II [≥ 30.0 kg/m²]: aHR 0.80, 95% CI 0.72-0.90) and transitioning from normal BMI to obesity (aHR 0.79, 95% CI 0.63-0.99) were associated with reduced lung cancer risk. Stratified analyses revealed stronger associations among men and ever smokers. Persistent obesity and BMI gain were associated with reduced risk in both men and women, whereas persistent underweight (aHR 1.24; 95% CI 1.14-1.35) and transitioning from normal BMI to underweight (aHR 1.27; 95% CI 1.17-1.39) were associated with increased risk only in men. Persistent obesity and BMI gain were associated with lower lung cancer risk in never-smokers as well as smokers, but persistent underweight (aHR 1.34, 95% CI 1.22-1.47) elevated lung cancer risk only in smokers. Age and menopausal status further modified the associations. Persistent obesity and BMI gain were protective, whereas underweight and BMI loss elevated lung cancer risk in men and smokers. Registry and the Registration no: NA.

Protein phosphorylation is a central post-translational modification regulating cellular signaling, frequently dysregulated in cancer. Mass spectrometry (MS)-based phosphoproteomics has emerged as a powerful approach to systematically profile phosphorylation events, thereby revealing aberrant kinase activity and therapeutic vulnerabilities that are not captured by genomic or transcriptomic analyses. Recent advances across the workflow-including optimized sample preparation and phosphopeptide enrichment, isotope- or label-free quantitative strategies, high-resolution mass spectrometry platforms, specialized algorithms for site identification and quantification, and integrative informatics analyses-have enabled the detection of tens of thousands of phosphorylation sites even from small clinical specimens. These developments have facilitated the characterization of signaling pathways across diverse cancer types, leading to the identification of targetable kinases and informing therapeutic strategies. In this review, we highlight studies that employed phosphoproteomic analyses of clinical specimens or patient-derived cancer cells to delineate signaling characteristics and to propose and validate therapeutic targets. Collectively, MS-based phosphoproteomics is poised to become a cornerstone of precision oncology. By enabling comprehensive and quantitative mapping of phosphorylation events, this technology allows mechanistic dissection of cancer signaling pathways and uncovers therapeutic vulnerabilities that may be exploited with targeted agents.