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Gabriella Sozzi



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    MA05 - Lung Cancer Screening (ID 174)

    • Event: WCLC 2020
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MA05.03 - Differential Frequency of Blood Immune Cells as Biomarkers for Risks Assessment in bioMILD Lung Cancer Screening Trial (ID 2197)

      11:45 - 12:45  |  Presenting Author(s): Gabriella Sozzi

      • Abstract
      • Presentation
      • Slides

      Introduction

      The role of adaptive and innate systemic immunity in lung carcinogenesis is poorly understood both in murine and clinical settings. Nevertheless, studying peripheral blood immune cells could provide insights into the pathogenesis of this process and allow the identification of novel biomarkers for early diagnosis and intervention. In line with this hypothesis is our previous finding that circulating microRNAs deriving from peripheral immune cells compose a three level miRNA signature risk Classifier (high, intermediate, low MSC) able to predict cancer development in heavy smokers. In this study we aimed to test whether differential frequencies of specific immune cell subsets in the peripheral blood of subjects enrolled in the bioMILD screening trial could help identifying high risk subjects and implement the accuracy of the MSC test.

      Methods

      Peripheral blood mononuclear cells (PBMC) prospectively isolated and stored from blood of volunteers enrolled in the bioMILD screening trial were analyzed by multiparametric flow cytometry (Cytoflex) using a total of 23 antibodies specific for markers encompassing monocyte and myeloid-derived suppressor cells (MDSC) subsets, regulatory T cells, cytolytic NK cells and activated/exhausted/hyperexausted T cells. To maximize the chances of detecting differential phenotypic patterns, the analysis was initially performed in a first training set of samples of the bioMILD trial including 20 Low Dose Computed Tomography (LDCT)-detected lung cancers and 20 matched cancer-free heavy smokers controls. Data were then validated in PBMC from 80 LDCT-detected lung cancer patients and 80 matched (1:1) cancer-free controls of the bioMILD trial. The C-reactive protein (CRP) plasma level was also measured in all subjects as inflammation marker.

      Results

      An increase of pro-angiogenic monocytes (CD14+CX3CR1+) and monocytic-MDSC (M-MDSC, CD14+HLA-DRneg) was observed in the patients group compared to controls. Conversely, intermediate monocytes (CD14+CD16+), which are associated with cancer immunosurveillance, and activated cytotoxic T (CD3+CD8+PD-1+) were instead reduced in lung cancer patients compared to controls. The plasma level of CRP did not differ in cases vs controls and showed no correlation with any of the analyzed immune cell subpopulations.The majority of these cell subsets were able to discriminate patients and controls independently from MSC risk level. However, specific cell subsets were differentially expressed in MSC high compared to low/intermediate risk patients. Among them, hyper-exhausted T cells (CD3+CD8+PD-1+LAG3+) and M-MDSC were increased in MSC high risk patients, while CD16highCD56+CD3+ NKT cells, protective elements mediating antibody-dependent cell cytotoxicity, were instead reduced.

      Conclusion

      Altogether, these findings suggest that MSC risk might associate with a immunosuppressed systemic immunity that could predispose to lung carcinogenesis. Hence, the characterization of the peripheral myeloid/lymphoid compartments can help distinguishing lung cancer screening cases and controls and may thus implement the accuracy of the blood miRNA-based MSC test.

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    P33 - Pathology - Immunotherapy Biomarker (ID 101)

    • Event: WCLC 2020
    • Type: Posters
    • Track: Pathology, Molecular Pathology and Diagnostic Biomarkers
    • Presentations: 1
    • Moderators:
    • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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      P33.01 - Circulating Extracellular Vesicles as Biomarkers for Immune-Checkpoint Inhibitors in Advanced NSCLC (ID 2311)

      00:00 - 00:00  |  Author(s): Gabriella Sozzi

      • Abstract
      • Slides

      Introduction

      Programmed death ligand-1 (PD-L1) expression is the only predictive biomarker in clinical practice for immune-checkpoints inhibitors (ICI) in NSCLC. Even if ICI efficacy is higher in PD-L1 strong positive tumours (Tumour Proportion Score, TPS>50%), also patients (pts) with low (TPS 1-49%) or absent (TPS<1%) PD-L1 expression can achieve a durable benefit. Extracellular vesicles (EVs) were used as biomarkers for cancer progression and could express PD-L1 on their surface (EVs-PD-L1). The main aim of this study was to evaluate EVs and EVs-PD-L1 in advanced NSCLC pts with low or absent TPS in order to find biomarkers for ICI in this pts subgroup.

      Methods

      EVs were isolated using ultracentrifuge from plasma of advanced NSCLC pts treated with ICI at our Institute. Pts were classified in responders (R) if they achieved a complete or partial response using RECIST 1.1 criteria, non-responders (NR) otherwise. EVs-PD-L1 was assessed by flow cytometry (FC). T cells of healthy donors were isolated and stimulated with CD3/CD28 Beads in presence of patients derived EVs, and analyzed by FC.

      Results

      Plasma samples were prospectively collected from 61 pts: 23 (37.7%) TPS low, 38 (62.3%) TPS absent, treated with ICI as first (n=23) or further (n=38) line; 19.7% were R, 80.3% NR. EVs-PD-L1 did not correlate with tumour PD-L1 expression. Stratifying baseline circulating EVs-PD-L1 levels according to median value, higher values were related to worse progression free survival (median: 2.2 vs 3.8 months, HR 1.78, 95%CI 1.03-3.08, p=0.036), without significant difference in overall survival (median: 8.3 vs 15.7 months, HR 1.50, 95%CI 0.79-2.88, p=0.213). In 20 patients (10 R, 10 NR), evaluated during ICI treatment (range: 3-13 weeks), EVs-PD-L1 levels increased in R compared to NR (PD-L1 fold change: R= 1.89 ± 0.24 vs NR= 0.91 ± 0.15; p<0.01). EVs had larger size in NR compared to R (mean size: R 149 ± 5.5 nm vs NR 169 ± 5.1 nm; n=6 for each group; p<0.05). No differences were observed in total particles count and expression of EVs-markers. Profiling 37 specific cell-type surface markers, Epcam surface expression was increased on R-EVs surface (median fluorescence: R=2114 vs NR=540, p<0.05), suggesting an epithelial origin of these EVs. We cultured in vitro CD8 T cells and CD4 T cells with EVs isolated from NR (n=12) or R (n=8) pts. EVs from both cohorts increased T cell proliferation compared to control T cells stimulated alone. Compared to NR-EVs, R-EVs induced higher T cell activation, evaluated as IFNγ and Granzyme B production, and reduced the frequency of CD4 Treg within cultures. No significant differences in checkpoint receptors expression on T cell surface (PD1, Tim3, Vista, Lag3) were detected.

      Conclusion

      Plasma EVs from NSCLC pts treated with ICI showed different features in terms of size, surface markers and activation of T cells. Increased T cell activation induced by R-EVs might reflect the presence of an activated immune-status in these pts. EVs-PD-L1 levels, assessed at baseline and during treatment, could represent a promising biomarker for ICI in NSCLC. Further studies including also PD-L1 TPS>50% NSCLC pts are warranted.

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