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Shengxiang Ren



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    JICC01 - Joint IASLC-CAALC-CSCO Session: The Truth and Myth of Oral Anti-VEGFR Inhibitors for Advance NSCLC (ID 276)

    • Event: WCLC 2020
    • Type: Workshop
    • Track: N.A.
    • Presentations: 1
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      JICC01.09 - Small Molecule Anti-VEGFR Combination with PD-1/PD-L1 Blockades: New Hope? (ID 4268)

      07:00 - 09:00  |  Presenting Author(s): Shengxiang Ren

      • Abstract

      Abstract not provided

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    MA13 - Tumor Biology: Focus on EGFR Mutation, DNA Repair and Tumor Microenvironment (ID 214)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Tumor Biology and Systems Biology - Basic and Translational Science
    • Presentations: 1
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      MA13.06 - Deciphering the Characterization of Tumor Microenvironment in EGFR-Mutated Non-Small Cell Lung Cancer (ID 3816)

      16:45 - 17:45  |  Author(s): Shengxiang Ren

      • Abstract

      Introduction

      Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood.

      Methods

      An established computational approach (CIBERSORT) to gene expression profiles of 402 lung adenocarcinoma from TCGA database was applied to infer the proportions of 22 subsets of immune cells in EGFR mutated and wild-type tissue samples. Primary NSCLC resections and peripheral blood of advanced NSCLC patients with determined EGFR status were collected and analyzed the subtypes of immune cells and T cell function via flow cytometry. Pre-treatment and one-cycle of immunotherapy plasma levels of 10 cytokines were measured using Meso Scale Discovery (MSD) in patients treated with immunotherapy. Association between EGFR signaling pathway and IL-10 mRNA expression was analyzed via PCR and western blotting. In vitro re-stimulation model of human CD8+T cells isolated from peripheral blood was used to analyze the impact of different dose of IL-10 on T cells.

      Results

      EGFR-WT tumors were associated with higher proportions of CD8+T (p<0.001) cells and activated memory CD4+ T cells (p<0.001).Transcriptome profiling revealed that lymphocyte activation or functions markers were highly expressed in EGFR-WT tumor. In primary NSCLC resections, EGFR-MUT tumors had lower proportion of CD8+Ki67+T cells (p=0.003). Functional or activated subsets of CD8+T cells, such as CD38+HLA-DR+ and GranzymeB+Ki67+ were also significantly less infiltrated in EGFR-MUT tumors (p=0.016, p=0.013, respectively).CD39, which was recently reported as a novel marker to distinguish bystander TILs (CD39-CD8+) was highly expressed in EGFR-MUT tumors (p=0.012). Similarly, treatment-naïve advanced EGFR-WT patients also had higher percentage of CD8+T cells expressing CD39 in peripheral blood. In addition, CD8+CD39+T cells subset was associated with higher level of Ki67, GranzymeB+Ki67+, PD-1+Ki67+and CD38+HLA-DR+ compared with CD39-T cells. Intratumoral level of IFN-γ, IL-10, IL-1 β, IL-4 was significantly lower in EGFR-MUT tumors compared with WT tumors. To further investigate the role of CD8+T cells expression CD39 and 4 differentially expressing cytokines, we also obtained PBMC from advanced NSCLC patients who received anti-PD1 treatment. Only IL-10 and CD39 were associated with immunotherapy response. In vitro study, 7 tumor cell lines were cocultured with CD8+T cells isolated from healthy donors. CD39+expressing CD8+T cells were significantly increased in the presence of EGFR-WT cell lines than EGFR-MUT cell lines. Also, higher IL-10 was associated with increased proliferation, cytotoxicity of T cells and CD39 expression in dose-dependent manner. To investigate the association of EGFR signaling and IL-10 expression, we added gefitinib in EGFR mutated cell lines and EGF in EGFR-WT cell lines. IL-10 mRNA expression was significantly increased after blocking EGFR signaling pathway and decreased after reactivation of EGFR pathway.

      Conclusion

      Poor response to anti-PD-1 treatment in EGFR patients could be attributed to:1) non-inflammed TME with lower percentage of activated or functional T cell subsets; 2) the abundance of CD39– CD8+ T cells in EGFR-mutated patients. Additional IL-10 could possibly reinvigorate CD8+CD39+T cells to potential anti-PD1 efficacy in EGFR-mutated patients.

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    P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P14.08 - Baseline Nlr and Plr Could Predict Clinical Outcomes in Patients With NSCLC Treated With ICIs (ID 1793)

      00:00 - 00:00  |  Author(s): Shengxiang Ren

      • Abstract

      Introduction

      Immune checkpoint inhibitors(ICIs) has become an important treatment for lung cancer. However, there are shortcomings in the treatment of ICIs. First, the effective rate of ICIs monotherapy is not high. Second, ICIs may bring adverse immune reactions to patients. Scientists hope to find biomarkers that predict the efficacy of immunotherapy. Unfortunately, the current biomarkers for the efficacy of ICIs are only tumor PDL-1 expression levels and TMB. The detection of these biomarkers often requires invasive procedures. Therefore, it is very important to discover a biomarker that is noninvasive and inexpensive to predict the efficacy of ICIs.

      Methods

      We retrospectively reviewed 95 patients with stage IV NSCLC who were treated with ICIs (pembrolizumab, nivolumab, atezolizumab, SHR-1210).baseline complete blood count , including white blood cell (WBC), absolute neutrophil count (ANC), platelet count and absolute lymphocyte count (ALC) to calculate the neutrophil-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)] were extracted from medical records. Derived NLR (dNLR) was calculated as dNLR = ANC/(WBC − ALC). C3 complete blood count (defined as the results obtained before Cycle 3 of ICIs) was also collected and calculated in the present study. correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves.

      Results

      In univariate analysis, Patients with baseline NLR ≥5 had similar ORR (30.4% versus 33.3%, P=0.796) and median PFS compared to those with NLR <5 (6.7 versus 7.1 months, HR, 1.01, 95% CI, 0.55-1.87; P=0.969) . Patients with C3 NLR <5 (84.4%, 76/90) had better ORR than those with C3 NLR ≥5 (38.2% versus 7.1%, P=0.030). There was also a trend towards better median PFS in patients with C3 NLR <5 but lack of statistical significance (7.7 versus 5.5 months, HR, 1.70, 95% CI, 0.90-3.22; P=0.120).Patients who had increased NLR (n=29, 32.2%) had inferior ORR (17.2% versus 41.0%, P=0.026) and median PFS (5.5 versus 8.5 months, HR, 1.87, 95% CI, 1.09-3.21; P=0.022) than those who had decreased NLR (n=61, 67.8%) . Baseline PLR was not associated with clinical outcomes of ICI therapy. There was a trend towards better ORR (20.0% versus 27.8% versus 40.9%, P=0.296) and median PFS (5.5 versus 7.0 versus 8.3 months, P=0.105) in patients lower C3 PLR but lack of statistical significance. Patients who had decreased PLR (n=47, 52.2%) had better ORR (42.6% versus 23.3%, P=0.052) and median PFS (11.8 versus 5.5 months, HR, 2.28, 95% CI, 1.32-3.94; P=0.003) than those who had increased PLR (n=43, 47.8%).Patients who had both decreased NLR and PLR had better ORR (47.4% versus 28.1% versus 15.0, P=0.034) and prolonged median PFS (11.8 versus 5.5 versus 5.6 months, P=0.003) than patients with either increased NLR or PLR or both increased NLR and PLR.

      Conclusion

      Dynamic changes of NLR and PLR were associated with clinical outcomes. NLR and PLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with NSCLC.

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    P47 - Small Cell Lung Cancer/NET - Biology / Translational (ID 234)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P47.02 - CCL19 Associates with Inferior Prognosis in Patients with SCLC Through Promoting Invasion and Metastasis (ID 1739)

      00:00 - 00:00  |  Author(s): Shengxiang Ren

      • Abstract

      Introduction

      Small cell lung cancer(SCLC) is a systemic disease and majority have metastasis at the initial diagnosis. Therefore, better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical outcome.

      Methods

      RNA-seq was used to identify the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes. Function assays and Western blotting were carried out to investigate the mechanism of CCL19 promote metastasis. Co-incubation and flow cytometry used to detect the impact of CCL19 on CD8+T cells function. Plasma CCL19 was detected by ELISA. Kaplan–Meier was used to perform survival analysis in patients.

      Results

      Four chemokines(CCL19,CCL21,CCL8,CCR1) had significantly different expression between primary SCLC lesion and metastatic LN. CCL19 was chose for further investigation because its mRNA expression was significantly higher in four SCLC cell lines(H446, H69, H82, H196) than normal bronchial epithelial cell line(Beas-2b) when compared with other three chemokines. CCL19 silencing significantly inhibited SCLC cell migration, invasion, proliferation and angiogenesis abilities. Mechanistically, we identified CCL19 promoted SCLC metastasis by MAPK-ERK signaling pathways. Furthermore, tumor-derived CCL19 biologically inhibited the function of CD8+ T cells with lower percentage of CD8+Ki67+ and CD8+GZMB+ T cells, whereas percentage of CD8+PD1+ T cells increased. Moreover, plasma higher CCL19 concentration was associated with late lymph node metastasis(Training cohort p=0.044, Validation cohort p=0.020) and shorter overall survival(Training cohort p=0.040, Validation cohort p=0.047) in SCLC patients.figure1.jpgfigure2.jpg

      Conclusion

      CCL19 promoted tumor progression and metastasis through MAPK/ERK signaling pathways and inhibited the function of CD8+ T cells. Its expression was associated with metastasis and poor prognosis in patients with SCLC, suggesting CCL19 might be served as a potential target for SCLC.

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    P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Targeted Therapy - Clinically Focused
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P76.07 - Metformin Enhances the Efficacy of EGFR-TKIs in Advanced Non-Small Cell Lung Cancer Patients With Type 2 Diabetes Mellitus (ID 897)

      00:00 - 00:00  |  Author(s): Shengxiang Ren

      • Abstract

      Introduction

      Lung cancer remains the leading cause of cancer-related mortality around the world. Despite epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) therapy have shown remarkable clinical efficacy in non-small cell lung cancer (NSCLC) patients, resistance is almost inevitable and is still a major obstacle. Studies have suggested that the prolonged use of metformin, a common oral anti-diabetes agent, also an IGF-1R inhibitor, is associated with survival benefits among NSCLC Type 2 diabetes mellitus (T2DM) patients. However, the clinical efficacy of metformin and EGFR-TKIs in combination, especially third-generation TKIs, on NSCLC patients with T790M mutation has not been well validated. Therefore, we retrospectively reviewed the effect of metformin use on the clinical efficacy of EGFR-TKIs in NSCLC patients with T2DM, and we also carried out in vitro experiment to demonstrate the effects of metformin in EGFR-TKI resistant cell lines in aspect of proliferation and apoptosis.

      Methods

      We retrospectively reviewed clinicopathological characteristics and response of NSCLC patients with type 2 diabetes mellitus (T2DM) who received EGFR-TKIs treatment. Therapeutic outcome including objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) of first-line EGFR-TKIs and second-line osimertinib were compare between patients received metformin and other anti-diabetes drugs. In addition, the effect of metformin on gefitinib-resistant cell line PC9R and osimertinib-resistant cell line PC9R/OR was examined in vitro using Cell Counting Kit-8, and apoptosis analysis, the IC 50, apoptosis rate and combination index (CI) was calculated.

      Results

      In fist-line EGFR-TKIs treatment, ORR in metformin use group was significantly higher (85.7% vs. 47.4%, p=0.001). The PFS1 and OS1 in metformin use group were significantly longer (21.6 months vs. 9.2 months, p =0.000; 48.4 months vs. 36.6 months, p =0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs with T790M. In vitro analysis, metformin showed synergistic interaction both with gefitinib in PC9R (CI=0.77) and with osimertinib in PC9R/OR (CI=0.77) in proliferation inhibition analysis. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs in vitro (p<0.05).

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      Conclusion

      The results of our study suggest metformin use could be beneficial to NSCLC patients with T2DM treated with either first-line EGFR-TKIs or second-line osimertinib treatment.