Biology subjects

Ripley, R. T.

Publications and source records attributed to Ripley, R. T..

5 recordsLinked to original sources

bioRxiv2026

Tumor-infiltrating natural killer cell profiling for therapeutic stratification in patients with resectable non-small cell lung cancer

ObjectiveNeoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with NSCLC, despite a high risk for surgical morbidity, show enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could guide treatment strategies. MethodsSingle-cell RNA sequencing (scRNAseq) was performed on 61 lung tissues from non-smokers and smokers to identify smoking-related immune compositions. The scRNAseq data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy followed by surgery were used for in silico cellular deconvolution and outcome analyses. ResultsAmong 135 lung cellular phenotypes, two natural killer (NK) cell subsets were strongly associated with smoking and chronic obstructive pulmonary disease (COPD) severity. "Stress-responsive" NK (NKSR) cells exhibited immature features and cytokine-responsive features, and "Adaptive and immunoregulatory NK" (NKAIR) cells showed mature features and elevated multiple immune checkpoint expression. High intratumoral NKSR cells correlated with improved survival after surgery, particularly in current smokers. Conversely, tumors with low NKSR and high NKAIR cells responded more favorably to neoadjuvant chemoimmunotherapy. ConclusionsIntratumoral NK cell phenotyping may aid in therapeutic stratification in patients with NSCLC. NKSR cell preservation predicts benefit from upfront surgery, while NKAIR cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These NK cell profiles may help optimize treatment by balancing therapeutic benefit and risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/696292v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@168bc03org.highwire.dtl.DTLVardef@10fa947org.highwire.dtl.DTLVardef@132a92dorg.highwire.dtl.DTLVardef@100e4a4_HPS_FORMAT_FIGEXP M_FIG C_FIG Central Picture O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/696292v1_ufig2.gif" ALT="Figure 2"> View larger version (21K): org.highwire.dtl.DTLVardef@1a2d3b4org.highwire.dtl.DTLVardef@f8f84borg.highwire.dtl.DTLVardef@17510bcorg.highwire.dtl.DTLVardef@9da763_HPS_FORMAT_FIGEXP M_FIG C_FIG NK cell profiling for treatment stratification in resectable NSCLC Central MessageTumor-infiltrating NK cell profiling identifies distinct immune phenotypes that can inform personalized treatment strategies in resectable NSCLC. Perspective statementAbundance of intratumoral stress-responsive NK cells predicts favorable outcomes after upfront surgery, whereas enrichment of adaptive and immunoregulatory NK cells suggests greater benefit from neoadjuvant chemoimmunotherapy. These findings support incorporating NK-cell profiling into preoperative decision-making to optimize therapy selection and balance risks in the high-risk surgical population.

immunology↗

bioRxiv2025

GASPS: A Multi-Omics Framework for Defining Genomic Aberration-Driven Signatures and Predicting Patient Outcomes in Lung Cancer

Lung cancer is the most common cause of cancer-related death worldwide. Recent advancements in targeted therapies and immunotherapies have achieved remarkable success. However, patient responses to treatments with lung cancer vary substantially. The mutation status of driver genes can direct personalized treatment, but their prognostic value and treatment efficacy are limited. In this study, we developed a statistical framework named Genomic Aberration-Derived Signature for Patient Stratification (GASPS) to characterize the transcriptomic deregulation of driver genomic aberrations and stratify patients. By applying GASPS to The Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) data, we developed gene signatures for 38 driver genomic aberrations, including gene mutations, amplifications, and deletions. These signatures were applied to independent lung cancer transcriptomic datasets containing a total of 2,226 patient samples. Our results indicated that these driver gene signatures are much more prognostic than their corresponding genomic mutations. Interestingly, the two EGFR-related signatures characterizing EGFR mutation and amplification, respectively, exhibited contrasting associations with prognosis, treatment response, and immune infiltration in the tumor microenvironment. Moreover, the STK11 mutation signature, rather than the mutation status, was found to be predictive of the response and long-term benefit of patients treated with immune checkpoint blockade therapy in lung cancer. This framework is readily applicable to most cancer types using existing data to improve prognostic risk assessment and treatment efficacy by guiding personalized therapies.

bioinformatics↗

bioRxiv2025

Gene signatures characterizing driver mutations in lung squamous carcinoma are predictive of the progression of pre-cancer lesions

Patients with lung squamous cell carcinoma (LUSC) are often diagnosed at advanced stages, limiting opportunities for early intervention. LUSC develops through a multistep progression from low-grade lesions to high-grade lesions, including carcinoma in situ (CIS), of which approximately half progress to invasive cancer while the other half regress. Although frequent mutations and copy number alterations have been documented in LUSC and observed in precursor lesions, their prognostic significance in precancerous stages remains largely unexplored. In this study, we leveraged gene expression data from LUSC tumors in The Cancer Genome Atlas (TCGA) to derive transcriptional signatures corresponding to 34 key driver genomic aberrations, including mutations, amplifications, and deletions. These tumor-derived gene signatures were then applied to precancerous lesion datasets to assess their ability to characterize developmental stages and predict progression risk. We found that many of these signatures increased progressively across lesion stages, reflecting their roles in early tumorigenesis. In particular, several signatures accurately predicted which CIS lesions would progress to invasive cancer. Furthermore, these signature scores were more strongly associated with patient prognosis in LUSC than the presence of genomic aberrations alone. We also examined the relationship between driver-associated signatures and the tumor immune microenvironment. Signature scores were significantly correlated with immune features such as immune cell infiltration and immune checkpoint gene expression, including CD274 (PD-L1). Interestingly, these associations varied across lesion stages, indicating dynamic immune interactions during cancer evolution. Together, our findings demonstrate that tumor-derived driver gene expression signatures provide valuable insight into the biology and progression risk of precancerous lesions, offering potential utility for early detection and intervention strategies in LUSC. Novelty and ImpactIn this study, we developed gene expression signatures using lung squamous cell carcinoma (LUSC) transcriptomic and genomic data and apply them to characterize precancerous lesions. These signatures showed high performance in predicting the progression risk of carcinoma in situ (CIS), offering a valuable tool for personalized prevention and early intervention in LUSC. These findings have the potential to improve early lung cancer detection and provide new insights into the tumor microenvironment in the context of precancer evolution of LUSC.

bioinformatics↗

bioRxiv2021

SMARCA4 regulates spatially restricted metabolic plasticity in 3D multicellular tissue

SWI/SNF and related chromatin remodeling complexes act as tissue-specific tumor suppressors and are frequently inactivated in different cancers. Although many regulatory activities of SWI/SNF have been identified using 2D cell culture, the effects of SWI/SNF alterations in more complex 3D tissues have remained poorly understood. Here we employed 3D cell culture conditions that yield transcriptomic states mirroring primary lung adenocarcinoma (LUAD) specimens better than 2D culture. By analyzing spatial patterns of gene expression and DNA accessibility in 3D spheroids using single-cell RNA-seq and ATAC-seq, we find that the SWI/SNF ATPase SMARCA4 (BRG1) induces state-specific changes to DNA accessibility that influence spatially heterogeneous expression patterns and metabolism. In 3D conditions, SMARCA4 promotes accessibility for AP-1 transcription factors, including ATF3, a regulator of metabolism and repressor of NRF2 antioxidant signaling. These changes reduce expression of SLC7A11 in a distinct portion of cells, which sensitizes A549 spheroids to cell death via ferroptosis under oxidizing conditions. Consistent with these results, we find that SMARCA4 alterations are associated with derepression of NRF2 targets in human tumors independently of NRF2/KEAP1 status. Our work reveals new 3D-specific features and unanticipated spatial complexity associated with chromatin remodeling in multicellular tissues.

systems biology↗

bioRxiv2021

Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma

BackgroundDespite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM. MethodsWe generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model. ResultsImmunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion of CDKN2A was highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome by CDK4/6 inhibition, we tested whether CDK4/6 inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived from Cdkn2a(-/-) AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration of CDK4/6 inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 or CDK4/6 inhibitor alone. ConclusionsWe identified a novel therapeutic target, CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials of CDK4/6 inhibitors in the more than 40% of patients with MPM who demonstrate loss of CDKN2A.

immunology↗