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J.J. Lee



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    OA20 - Immunotherapy and Markers (ID 401)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
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      OA20.05 - The Influence of Neoadjuvant Chemotherapy, on Immune Response Profile in Non-Small Cell Lung Carcinomas (ID 5738)

      11:00 - 12:30  |  Author(s): J.J. Lee

      • Abstract
      • Presentation
      • Slides

      Background:
      The clinical efficacy observed with PD-1/PD-L1 inhibitors in non-small cell lung carcinoma (NSCLC) has prompted to characterize the immune response in lung tumors treated with chemotherapy. Our goal was to determine the characteristics of immune microenvironment of localized, surgically resected, NSCLCs from patients who received and did not receive neo-adjuvant chemotherapy. Using multiplex immunofluorescence (mIF) and image analysis, we investigated PD-1/PD-L1 expression, and quantified tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs).

      Methods:
      We studied formalin-fixed and paraffin embedded (FFPE) tumor tissues from 111 stage II and III resected NSCLC, including 61 chemonaïve (adenocarcinoma, ADC=33; squamous cell carcinoma, SCC=28) and 50 chemotherapy-treated (ADC=30; SCC=20) tumors. mIF was performed using the Opal 7-color fIHC Kit™ and analyzed using the Vectra™ multispectral microscope and inForm™ Cell Analysis software (Perkin Elmer, Waltham, MA). The markers studied were grouped in two 6-antibody panels: Panel 1, AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD4, CD8 and CD68; and Panel 2, AE1/AE3, PD1, Granzyme B, FOXP3, CD45RO and CD57.

      Results:
      Positive PD-L1 expression (>5%) in malignant cells (MCs) was detected in 48% (n=53/111) of NSCLCs. Overall, chemotherapy-treated tumors showed significantly higher percentages of MCs expressing PD-L1 (median, 18.2%) than chemo-naïve cases (median, 1.8%; P=0.033). Higher densities of inflammatory cells expressing granzyme B (P=0.036), CD57 (P=0.001) and PD-1 (P=0.016) were detected in chemotherapy-treated NSCLCs compared with chemo-naïve tumors. In contrast, lower densities of FOXP3-positive regulatory T cells were detected in chemotherapy-treated tumors when compared with chemo-naïve cases (P=0.032). Following chemotherapy ADCs exhibited significantly higher levels of CD57-positive cells (P<0.0001) and lower density of FOXP3-positive cells (P=0.002) than chemo-naïve tumors. Chemotherapy-treated SCCs demonstrated higher density of PD-1-positive cells than chemo-naïve tumors (P=0.004). In chemotherapy-treated cancers, lower levels of CD4 helper T positive cells and tumor associated macrophages (TAMs) CD68-positive cells were associated with worse overall survival (OS; P=0.04 and P=0.005, respectively) in univariate analysis. In chemotherapy-treated ADC patients, lower levels of CD68-positive (P=0.010) and higher levels of FOXP3-positive cells correlated with worse OS (P=0.044).

      Conclusion:
      We developed a robust mIF panel of 10 markers to study inflammatory cells infiltrates in FFPE NSCLC tumor tissues. Chemotherapy-treated NSCLCs exhibited higher levels of PD-L1 expression and T cell subsets compared to chemo-naïve tumors, suggesting that chemotherapy activates specific immune response mechanisms in lung cancer. (Supported by CPRIT MIRA and UT Lung SPORE grants, and MD Anderson Moon Shot Program).

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    P2.01 - Poster Session with Presenters Present (ID 461)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.01-061 - Image Analysis-Based Expression of Nine Immune Checkpoints Identifies Distinct Immunoprofiling Patterns in Non-Small Cell Lung Carcinomas (ID 5548)

      14:30 - 15:45  |  Author(s): J.J. Lee

      • Abstract

      Background:
      The understanding of the co-expression of immune checkpoints in non-small cell lung carcinoma (NSCLC) is important to potentially design combinatorial immunotherapy approaches in this disease. We examined the expression of a panel of immune checkpoints markers by immunohistochemistry (IHC) and quantitative image analysis in a large cohort of surgically resected NSCLCs, and correlated those findings with patients’ clinicopathological features and tumors’ inflammatory cells infiltrate and molecular characteristics.

      Methods:
      We studied 225 formalin fixed and paraffin embedded (FFPE) tumor tissues from stage I-III NSCLCs, including 123 adenocarcinomas (ADC) and 83 squamous cell carcinomas (SCC), placed in tissue microarrays (TMAs). Nine immune checkpoints markers, 4 (PD-L1, B7-H3, B7-H4, IDO1) expressed predominantly in malignant cells (MCs), and 5 (ICOS, VISTA, TIM3, LAG3 and OX40) expressed mostly in stromal tumor associated inflammatory cells (TAICs). All IHC markers were examined using quantitative image analysis system (Aperio).

      Results:
      Using > median value of the immune checkpoint expressions as positive expression we observed that MCs H-score expressing PD-L1, B7-H3, B7-H4 and IDO1was higher in SCC than ADC, with 3 out of 4 markers showing statistically significant (P<0.05) differences. In contrast, density of TAICs expressing ICOS, VISTA, OX40, LAG3 and TIM3 was higher in ADC than SCC, with 3 out of 5 markers demonstrating significant (P<0.05) differences. Furthermore, we identified frequent co-expression of markers: a) 11% ADC (13/123) and 10% SCC (8/83) co-expressed 8 to 9 markers; b) 45% ADC (55/123) and 32% SCC (27/83) co-expressed 6 to 7 markers, c) 28% ADC (35/123) and 40% SCC (33/83) co-expressed 4 to 5 markers, and d) 16% ADC (20/123) and 18% SCC (15/83) co-expressed 2 to 3 markers. In ADC, higher number of TAICs expressing OX40 and lower levels of MCs expressing B7-H4 were detected in tumors with EGFR (median, 7.49 vs. 1.16, P=0.021) and KRAS (median, 6.88 vs. 0.67, P=0.033) mutation compared with wild-type tumors, respectively. Univariate analysis demonstrated that high B7-H4 and low OX40 expression in MCs and in TAICs respectively correlated with worse overall survival (OS; P=0.016 and P=0.037, respectively) in ADC patients.

      Conclusion:
      We detected different patterns of immune checkpoints expression in NSCLC with higher level of markers found in malignant cells of SCC and in stromal inflammatory cells of ADC. Immune checkpoints expression correlated with the outcome of NSCLC patients. Importantly, co-expression of several immune checkpoints is a frequent event in NSCLC (Supported by CPRIT MIRA and UT Lung SPORE grants).