Browsing by Author "Li, Wencheng"

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    c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities
    (MDPI, 2023-05-05) Liu, Yin; Smith, Margaret R.; Wang, Yuezhu; D’Agostino, Ralph, Jr.; Ruiz, Jimmy; Lycan, Thomas; Kucera, Gregory L.; Miller, Lance D.; Li, Wencheng; Chan, Michael D.; Farris, Michael; Su, Jing; Song, Qianqian; Zhao, Dawen; Chandrasekaran, Arvind; Xing, Fei; Biostatistics and Health Data Science, School of Medicine
    The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.
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    Genomic signature for oligometastatic disease in non-small cell lung cancer patients with brain metastases
    (Frontiers Media, 2024-09-17) Choi, Ariel R.; D’Agostino, Ralph B., Jr.; Farris, Michael K.; Abdulhaleem, Mohammed; Hunting, John C.; Wang, Yuezhu; Smith, Margaret R.; Ruiz, Jimmy; Lycan, Thomas W.; Petty, W. Jeffrey; Cramer, Christina K.; Tatter, Stephen B.; Laxton, Adrian W.; White, Jaclyn J.; Li, Wencheng; Su, Jing; Whitlow, Christopher; Xing, Fei; Chan, Michael D.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Purpose/objectives: Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease. Methods: Patients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher's exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression. Results: 130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03). Conclusions: Elucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.
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    IASLC grading system predicts distant metastases for resected lung adenocarcinoma
    (BMJ, 2025-05-25) Wang, Yuezhu; Smith, Margaret R.; Dixon, Caroline B.; D’Agostino, Ralph; Liu, Yin; Ruiz, Jimmy; Chan, Michael D.; Su, Jing; Mileham, Kathryn F.; Lycan, Thomas; Green, Mary E.; Hassan, Omer A.; Jiang, Yuming; Niazi, M. Khalid Khan; Li, Wencheng; Xing, Fei; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Aims: The International Association for the Study of Lung Cancer (IASLC) has proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, the efficacy of this grading system in predicting distant metastases in patients with LUAD remains unexplored. This study aims to assess the potential of the IASLC grading system in predicting the occurrence of brain and bone metastases in patients with resectable LUAD, thereby identifying individuals at high risk of post-surgery distant metastasis. Methods: We retrospectively analysed clinical data and pathological reports of 174 patients with early-stage LUAD who underwent surgical resection between 2008 and 2015 at our cancer center. Patients were monitored for 5 years, and their bone and brain metastasis-free survival rates were determined. Results: 28 out of 174 patients developed distant metastases in 5 years with a median overall survival of 60 months for metastasis-free patients and 38.3 months for patients with distant metastasis. Tumour grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. Receiver operating characteristic (ROC) curves were used to evaluate the predictive capabilities of the IASLC grading system and tumour stage for distant metastasis. Compared with the predominant pattern-based grading system, the IASLC grading system showed a better correlation with the incidence of distant metastasis and lymphovascular invasion. ROC analyses revealed that the IASLC grading system outperformed tumour stage in predicting distant metastasis. Conclusions: Our study indicates that the IASLC grading system is capable of predicting the incidence of distant metastasis among patients with early-stage invasive LUAD.
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    Modulation of oxidative phosphorylation and mitochondrial biogenesis by cigarette smoke influence the response to immune therapy in NSCLC patients
    (Elsevier, 2023-04) Wang, Yuezhu; Smith, Margaret; Ruiz, Jimmy; Liu, Yin; Kucera, Gregory L.; Topaloglu, Umit; Chan, Michael D.; Li, Wencheng; Su, Jing; Xing, Fei; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint blockade (ICB). However, only a subset of patients experience benefit after receiving ICBs. Therefore, it is of paramount importance to increase the response rate by elucidating the underlying molecular mechanisms and identifying novel therapeutic targets to enhance the efficacy of IBCs in non-responders. We analyzed the progression-free survival (PFS) and overall survival (OS) of 295 NSCLC patients who received anti-PD-1 therapy by segregating them with multiple clinical factors including sex, age, race, smoking history, BMI, tumor grade and subtype. We also identified key signaling pathways and mutations that are enriched in patients with distinct responses to ICB by gene set enrichment analysis (GSEA) and mutational analyses. We found that former and current smokers have a higher response rate to anti-PD-1 treatment than non-smokers. GSEA results revealed that oxidative phosphorylation (OXPHOS) and mitochondrial related pathways are significantly enriched in both responders and smokers, suggesting a potential role of cellular metabolism in regulating immune response to ICB. We also demonstrated that all-trans retinoic acid (ATRA) which enhances mitochondrial function significantly enhanced the efficacy of anti-PD-1 treatment in vivo. Our clinical and bioinformatics based analyses revealed a connection between smoking induced metabolic switch and the response to immunotherapy, which can be the basis for developing novel combination therapies that are beneficial to never smoked NSCLC patients.
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    Patterns of Failure Outcomes for Combination of Stereotactic Radiosurgery and Immunotherapy for Melanoma Brain Metastases
    (Wolters Kluwer, 2023-01-11) Abdulhaleem, Mohammed; Johnston, Hannah; D'Agostino, Ralph, Jr.; Lanier, Claire; Cramer, Christina K.; Triozzi, Pierre; Lo, Hui-Wen; Xing, Fei; Li, Wencheng; Whitlow, Christopher; White, Jaclyn J.; Tatter, Stephen B.; Laxton, Adrian W.; Su, Jing; Chan, Michael D.; Ruiz, Jimmy; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Background: Previous series have demonstrated central nervous system activity for immune checkpoint inhibitors (ICIs) and shown improved local control between stereotactic radiosurgery (SRS) and ICI for lung cancer brain metastases. Objective: To assess whether the addition of ICI to SRS for melanoma brain metastasis improves outcomes when compared with historical control group treated in the era before ICI availability. Methods: In this single institution retrospective series, outcomes of 24 patients with melanoma receiving concurrent ICI and SRS were compared with 111 historical controls treated before ICI era. Overall survival (OS) was estimated using the Kaplan-Meier method. Cumulative incidence of local and distant failures was estimated using a competing risk model that accounted for baseline differences using propensity score adjustments. Results: The median OS time was improved in patients receiving ICI compared with the historical control group (17.6 vs 6.6 months, hazard ratio [HR] = 0.056, P = .0005). Cumulative incidence at 1 year for local failure in the historical control and ICI groups was approximately 12.5% and 6.5%, respectively (HR = 0.25, P = .19), while cumulative incidence of distant brain failure in the historical control and ICI groups was approximately 48% and 28%, respectively (HR = 0.326, P = .015). Conclusion: Distant brain failure and OS were improved in patients receiving concurrent ICI with SRS compared with historical controls. Local failure trended in the same direction; however, owing to small sample size, this did not reach statistical significance. While these data remain to be validated, they suggest that patients with brain metastasis may benefit from concurrent use of ICI with SRS.
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    Patterns of Failure Outcomes for Combination of Stereotactic Radiosurgery and Immunotherapy for Melanoma Brain Metastases
    (Wolters Kluwer, 2023-03) Abdulhaleem, Mohammed; Johnston, Hannah; D'Agostino, Ralph, Jr.; Lanier, Claire; Cramer, Christina K.; Triozzi, Pierre; Lo, Hui-Wen; Xing, Fei; Li, Wencheng; Whitlow, Christopher; White, Jaclyn J.; Tatter, Stephen B.; Laxton, Adrian W.; Su, Jing; Chan, Michael D.; Ruiz, Jimmy; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    BACKGROUND: Previous series have demonstrated central nervous system activity for immune checkpoint inhibitors (ICIs) and shown improved local control between stereotactic radiosurgery (SRS) and ICI for lung cancer brain metastases. OBJECTIVE: To assess whether the addition of ICI to SRS for melanoma brain metastasis improves outcomes when compared with historical control group treated in the era before ICI availability. METHODS: In this single institution retrospective series, outcomes of 24 patients with melanoma receiving concurrent ICI and SRS were compared with 111 historical controls treated before ICI era. Overall survival (OS) was estimated using the Kaplan-Meier method. Cumulative incidence of local and distant failures was estimated using a competing risk model that accounted for baseline differences using propensity score adjustments. RESULTS: The median OS time was improved in patients receiving ICI compared with the historical control group (17.6 vs 6.6 months, hazard ratio [HR] = 0.056, P = .0005). Cumulative incidence at 1 year for local failure in the historical control and ICI groups was approximately 12.5% and 6.5%, respectively (HR = 0.25, P = .19), while cumulative incidence of distant brain failure in the historical control and ICI groups was approximately 48% and 28%, respectively (HR = 0.326, P = .015) CONCLUSION: Distant brain failure and OS were improved in patients receiving concurrent ICI with SRS compared with historical controls. Local failure trended in the same direction; however, owing to small sample size, this did not reach statistical significance. While these data remain to be validated, they suggest that patients with brain metastasis may benefit from concurrent use of ICI with SRS.
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    Targeting NTRK1 Enhances Immune Checkpoint Inhibitor Efficacy in NTRK1 Wild-Type Non-Small Cell Lung Cancer
    (American Association for Cancer Research, 2024) Smith, Margaret R.; Dixon, Caroline B.; Wang, Yuezhu; Liu, Yin; D’Agostino, Ralph, Jr.; Ruiz, Jimmy; Oliver, George; Miller, Lance D.; Topaloglu, Umit; Chan, Michael D.; Farris, Michael; Su, Jing; Mileham, Kathryn F.; Zhao, Dawen; Li, Wencheng; Sexton, Tammy; Lycan, Thomas; Haas, Karen M.; Grayson, Jason M.; Xing, Fei; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anticancer effects of immune checkpoint inhibitors (ICI). However, only 20% of the patients with NSCLC benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 patients with NSCLC who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss-of-function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS when compared with patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T-cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti-PD-1-treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating cross-talk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcome immunotherapy resistance in patients with NSCLC with NTRK1 wild-type. Significance: Inhibition of NTRK1 signaling confers sensitivity to immunotherapy by enhancing complement C3-mediated T-cell and macrophage functions, leading to improved responses to immune checkpoint inhibitors in patients with lung cancer with NTRK1 mutations.