Cancer Science最新文献

First-line atezolizumab combination therapies were approved for the treatment of metastatic non-small cell lung cancer (NSCLC) based on results from the global phase 3 trials IMpower130, IMpower132, and IMpower150. These trials reported 12-month overall survival (OS) rates of 60%-67% with atezolizumab combination therapy. J-TAIL-2 (NCT04501497), a prospective, multicenter, observational study, evaluated atezolizumab combination therapy in routine clinical practice in Japan. Patients ≥ 20 years old with NSCLC received atezolizumab plus carboplatin and nab-paclitaxel (atezo + CnP), atezolizumab plus carboplatin or cisplatin plus pemetrexed (atezo + PP), or atezolizumab plus bevacizumab plus carboplatin and paclitaxel (atezo + bev + CP) in clinical practice. The primary endpoint was the 12-month OS rate. Secondary endpoints included OS, progression-free survival, and subgroup analyses, including IMpower-unlike (did not meet the main eligibility criteria of each IMpower trial) and IMpower-like patients. In total, 814 patients were enrolled (atezo + CnP, n = 217; atezo + PP, n = 211; atezo + bev + CP, n = 386). The IMpower-unlike group included patients with Eastern Cooperative Oncology Group performance status ≥ 2, autoimmune disease, or interstitial lung disease. Twelve-month OS rates (95% confidence interval [CI]) were 62.9% (55.8-69.2), 72.1% (65.2-77.9), and 68.3% (63.2-72.9) with atezo + CnP, atezo + PP, and atezo + bev + CP, respectively. OS hazard ratios (95% CI) in the IMpower-unlike vs. -like subgroups were 1.36 (0.91-2.05), 1.08 (0.70-1.68), and 1.49 (1.09-2.06), respectively. No new safety signals were observed. Real-world efficacy and safety for each atezolizumab combination were comparable to those in the relevant IMpower trials.

Cancer-stromal interactions play important roles in the biology of various cancers, including lung adenocarcinoma. We aimed to comprehensively analyze the lung cancer interactome and identify the key ligand-receptor pairs involved in the aggressiveness of lung adenocarcinoma. Transcriptome data were obtained from xenografts of 11 lung cancer cell lines that represented the major driver mutations in lung adenocarcinomas. A quantitative dataset was constructed in both stroma-to-cancer and cancer-to-stroma directions using the cancer-stromal interactome analysis method. The prognostic value of each factor was evaluated using multiple datasets. Analysis of 24,250 stroma-derived mouse transcripts and 26,289 human cancer-derived transcripts identified 1150 cancer-stromal interactions, from which we selected 117 interactions based on the intensity score of ligand-stromal transcript levels. Further prognostic analysis using public databases led us to identify 21 ligand-receptor pairs, including well-known as well as less well-characterized ligand-receptor pairs. Therefore, we selected tumor necrosis factor superfamily member 12/tumor necrosis factor receptor superfamily member 12A as possible factors contributing to the aggressiveness of lung adenocarcinoma via cancer-stromal interactions; immunohistochemical analysis confirmed that these factors were expressed mainly in the stroma and cancer cells, respectively, in both xenografts and primary lung adenocarcinoma. In human clinical specimens, high tumor necrosis factor receptor superfamily member 12A expression significantly correlated with tumor size, invasive diameter, and stage. Thus, tumor necrosis factor superfamily member 12 and its receptor tumor necrosis factor receptor superfamily member 12A signaling axis may be potential candidates for therapeutic intervention for lung adenocarcinoma.

Advanced hepatic fibrosis is a major risk factor for cirrhosis and hepatocellular carcinoma (HCC), and it is required to identify a key mediator involved in intratumoral fibrosis and HCC development. Transcriptomic analysis of 372 HCC samples using publicly available datasets revealed that SPP1 was significantly upregulated in fibrotic HCC tissues and associated with unfavorable outcomes. Immunohistochemical analysis of 103 HCC tissues and single-cell RNA sequencing (scRNA-seq) analysis of 228,564 live cells identified SPP1 overexpression in HCC cells, which strongly correlated with intratumoral fibrosis. In xenograft models, HCC cells with SPP1 overexpression (SPP1-OE) exhibited enhanced fibrosis and tumor growth. Coculture assay demonstrated that SPP1-OE cells stimulated hepatic stellate cells (HSCs), and gene set enrichment analysis and differential gene expression analysis elucidated the activation of the Hedgehog signaling pathway and upregulation of GLI1 in HSCs. Cell-cell interaction prediction analysis using scRNA-seq data suggested that SPP1-CD44 signaling transduction might contribute to HSC activation. Pharmacological inhibition of GLI1 with the SMO inhibitor vismodegib suppressed HSC activation in vitro and reduced fibrosis and tumor growth in vivo. These findings indicate that SPP1 promotes intratumoral fibrosis and HCC progression through the SPP1-CD44-GLI1 axis, highlighting its potential as a prognostic biomarker and therapeutic target. Inhibition of SPP1-CD44-Hedgehog signaling may provide a promising strategy to mitigate fibrosis and improve HCC patient outcomes.

The impact of achieving progression-free survival at 24 months (PFS24) on subsequent survival in patients with diffuse large B-cell lymphoma (DLBCL) relative to the general population remains debatable. We assessed the impact of achieving PFS24 in newly diagnosed DLBCL patients using data from JCOG0601, a prospective study of DLBCL patients treated with R-CHOP. Among 409 eligible patients (median follow-up: 5.3 years), 334 (82%) achieved PFS24, whereas 66 (16%) did not. Patients who achieved PFS24 had significantly better overall survival (OS) than those who did not (median OS, not reached vs. 1.3 years; p < 0.001). Similar results were observed for PFS12 and PFS60. The OS for patients after achieving PFS24 or PFS60 was not markedly different from that of the age-, sex-, and calendar period-matched Japanese general population (PFS24: standardized mortality ratio [SMR] 1.29, 95% confidence interval [CI] 0.72-2.12, p = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, p = 0.55). Conversely, the OS for patients after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95% CI 1.59-3.22, p < 0.001). The primary cause of death among patients who achieved PFS12 was DLBCL, whereas the mortality rate from DLBCL among those who achieved PFS24 or PFS60 was less than 5%. Multivariable analysis showed that having two or more extranodal involvements (OR 2.76 [95% CI 1.39-5.46], p = 0.004) was the only significant risk factor for failing to achieve PFS24. Our findings suggest that PFS24 can serve as an early endpoint of OS in patients with DLBCL.

The global Phase 3 IMpower010 study (NCT02486718) evaluated atezolizumab versus best supportive care (BSC) after complete resection and adjuvant platinum-based chemotherapy in patients with stage IB-IIIA non-small cell lung cancer (NSCLC). We report updated efficacy and safety results from the disease-free survival (DFS) final and overall survival (OS) second interim analyses, with ≥ 5 years of follow-up in Japanese patients. Patients who received 1-4 21-day chemotherapy cycles after surgery were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤ 16 cycles) or BSC. Of 149 patients enrolled, 117 were randomized to the intention-to-treat (ITT) population (atezolizumab n = 59; BSC n = 58). At data cutoff (January 26, 2024), unstratified hazard ratios (HRs) (95% confidence interval [CI]) for DFS in the atezolizumab versus BSC arms were 0.54 (0.28-1.07) in the stage II-IIIA programmed death-ligand 1 (PD-L1) tumor cell (TC) ≥ 1% (n = 74), 0.64 (0.27-1.52) in the stage II-IIIA PD-L1 TC 1%-49% (n = 34), 0.52 (0.17-1.54) in the stage II-IIIA PD-L1 TC ≥ 50% (n = 40), 0.58 (0.34-1.00) in the stage II-IIIA all-randomized (n = 113), and 0.57 (0.34-0.98) in the ITT populations. OS remained immature; median OS was not reached in both treatment arms for all subgroups. Grade 3/4 adverse events occurred in 15 (26.8%) and 7 patients (12.1%) in the atezolizumab and BSC arms, respectively; no deaths were reported. In this exploratory subgroup analysis, adjuvant atezolizumab demonstrated numerically improved DFS and OS versus BSC in Japanese patients and was well tolerated, similar to the global IMpower010 population. Trial Registration: ClinicalTrials.gov identifier: NCT02486718.

Clinical development of crizotinib in children with ALK-positive anaplastic large cell lymphoma (ALCL) was advanced in the US but not in Japan. The objectives of phase 1 part of a clinical study in Japan were to assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of crizotinib in children with relapsed/refractory (R/R) ALK-positive ALCL or neuroblastoma (NB). Two dose levels (165 and 280 mg/m² twice daily (BID)) were planned to be evaluated. The aim of phase 2 part of the study was to assess the antitumor activity of crizotinib at the RP2D in children with R/R ALK-positive ALCL. Seven patients were eligible for phase 1 part, 5 with ALCL and 2 with NB. All 7 patients received crizotinib at a starting dose of 165 mg/m² BID, with 1 dose-limiting toxicity observed (grade 3 gamma-glutamyltransferase increased). The most common grade 3 or 4 adverse event was neutropenia (71%). The steady-state C_max and AUC_tau of crizotinib at 165 mg/m² BID were higher than expected. Considering the risk of a greater incidence of severe neutropenia, we decided that the 165 mg/m² BID be the RP2D without evaluation at 280 mg/m² BID. A total of 11 patients with ALK-positive ALCL were enrolled in the phase 2 part. The objective response rate was 72.7% (90% CI, 43.6%-92.1%). One patient permanently discontinued crizotinib due to disease progression. Crizotinib at 165 mg/m² BID was well tolerated and showed favorable antitumor activity in children with R/R ALK-positive ALCL. Trial Registration: UMIN-CTR: UMIN000028075.

Accurate primary tumor (pT) staging in muscle-invasive bladder cancer (MIBC) is crucial for treatment and prognosis. Current methods require time-consuming, labor-intensive microscopic evaluation by pathologists, with inherent interobserver variability. There is a need for AI-driven automated diagnosis of whole-slide images (WSI) to improve diagnostic efficiency while maintaining accuracy in pT staging. We obtained 281 H&E-stained WSI samples from the TCGA dataset for developing and validating a graph neural network (GNN)-based diagnostic model, and 83 additional samples from a hospital for external validation. The GNN method integrated multi-scale WSI data, evaluated using areas under the curve (AUC), accuracy, sensitivity, and specificity. A multi-scale attention mechanism was added to enhance model interpretability by capturing pT staging infiltration patterns. Diagnostic results were compared with those of three pathologists of varying expertise. We developed the multi-scale WSI-integrated GNN model for histopathological staging (T2/T3/T4) of MIBC. The model demonstrated excellent performance on external validation, achieving an AUC of 0.911 and an accuracy of 0.905. Interpretability analysis revealed distinct infiltration patterns for each T-stage, while diagnostic comparisons against both ground truth and three independent pathologists showed strong agreement, with a Cohen's kappa coefficient exceeding 0.876. The model developed based on graph neural network methods can integrate multi-scale information from whole-slide tissue images, allowing it to capture key infiltration patterns for muscle-invasive bladder cancer pT staging. This enables precise pT staging and visualizes the multi-scale tumor infiltration regions through attention scores, with accuracy showing strong consistency with expert pathologists.

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable success in treating hematological malignancies; however, antigen-positive relapse remains a significant obstacle to achieving sustained remission in B-cell acute lymphoblastic leukemia (B-ALL). To enhance the therapeutic efficacy of anti-CD19 CAR (CAR19)-T cells, we overexpressed CXCR4 in CAR19-T cells to improve their trafficking to bone marrow (BM), a key sanctuary for minimal residual disease. We engineered CAR19-T cells with overexpression of wild-type CXCR4 (CAR19/CXCR4^WT-T) or gain-of-function CXCR4 S338X mutant (CAR19/CXCR4^S338X-T). Both CAR19/CXCR4^WT-T and CAR19/CXCR4^S338X-T cells exhibited enhanced CXCR4 surface expression in vitro and in vivo compared to control CAR19-T cells, with the latter showing significantly superior improvements under all tested conditions, including engagement with CAR-specific antigens or CXCR4 ligand CXCL12. Upon engagement with CXCL12, CAR19/CXCR4^S338X-T cells, but not CAR19/CXCR4^WT-T cells, displayed significantly increased activation of ERK1/2 and AKT signaling pathways, as well as elevated transcription of TNF-α, IFN-γ, granzyme B, CDK6, and BCL2A1, along with strengthened effector functions, chemotaxis, and activation of anti-apoptotic pathways. Furthermore, CAR19/CXCR4^S338X-T cells demonstrated significantly improved migration to and retention in the BM accompanied by increased CD45RA⁺CCR7⁺ memory T cell populations, which correlated with enhanced anti-leukemic effects following injection into B-ALL-bearing mice. This study offers a potentially effective strategy to improve the functionality and durability of CAR-T cell responses in hematological malignancies.

Tumor tissues in pancreatic cancer develop with abundant cancer-associated fibroblasts (CAFs), promoting tumor progression. CAF-conditioned medium induces the expression of sushi domain-containing 2 (SUSD2) and enhances the invasive potential of pancreatic cancer cells. We showed that SUSD2 binds to integrin β1 and promotes pancreatic cancer cell motility by inducing phosphorylation of focal adhesion kinase (FAK), facilitating the formation of focal adhesion complexes in cells adhered to collagen 1 or fibronectin. Orthotopic transplantation of SUSD2-overexpressing human pancreatic cancer cell lines into the mouse pancreas enhanced liver metastasis in Panc-1 cells, whereas in KP2 cells, it increased primary tumor growth without promoting metastasis. In spheroid cultures of KP2 cells, forced SUSD2 expression elevated FAK phosphorylation independently of cell adhesion, suggesting that SUSD2 promotes cell proliferation even in non-metastatic cells. High SUSD2 expression in cancer cells contributes to tumor growth and metastasis, identifying SUSD2 as a potential therapeutic target in pancreatic cancer.