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Neda Kalhor



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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence (ID 13334)

      11:15 - 11:25  |  Author(s): Neda Kalhor

      • Abstract
      • Presentation
      • Slides

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

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    P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.04-22 - CD73 Immunohistochemical Expression in Malignant Cells and Correlation with Immune Infiltrate in Non-Small Cell Lung Carcinoma (NSCLC). (ID 11859)

      16:45 - 18:00  |  Author(s): Neda Kalhor

      • Abstract
      • Slides

      Background

      CD73 is potential novel target for lung cancer immunotherapy involved in the adenosine pathway that induces tumor microenvironment immunosuppression. We investigated the immunohistochemical (IHC) expression of CD73 in a large cohort of NSCLC and correlated with tumor’s clinical, pathological, molecular and immune cells infiltration data.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We examined 175 surgically resected stages I-III formalin-fixed and paraffin-embedded NSCLC tumors tissue microarrays, including 107 adenocarcinomas (ADC) and 68 squamous cell carcinomas (SqCC). For IHC, we used the anti-CD73 antibody (clone D7F9A, Cell Signaling Technology) and evaluated membrane (basolateral and luminal) expression in malignant cells. In a subset of cases, CD73 IHC expression was correlated with data available on: a) CD73 gene mRNA expression (Illumina arrays; n=91); b) EGFR and KRAS mutation status and mutational load (whole exome sequencing; n=104); and, c) density of tumor associated immune cells infiltration (CD3, CD4, CD8, CD68, CD45RO, CD57, FOXP3, and granzyme B) and immune checkpoints expression (PD-L1, PD-1, ICOS, TIM-3, IDO-1, B7-H3, B7-H4, VISTA and OX40) assessed by IHC and image analysis (n=172).

      4c3880bb027f159e801041b1021e88e8 Result

      ADC showed higher CD73 IHC expression than SqCC (P<0.0001). Pathological stage I ADCs showed higher CD73 expression than higher tumor stages (P=0.0419). Using any level of CD73 expression (>1%) CD73 was expressed in 73% and 40% of ADCs and SqCs, respectively. High expression (>50% of malignant cells) was detected in 35% of ADCs and 20% of SqCC. No other significant correlations with clinical-pathological variables, including patients’ outcome were found. Interestingly, ADCs with EGFR (P=0.04) and KRAS (P=0.02) mutation expressed higher CD73 levels than wild-type tumors. In ADC, CD73 IHC expression correlated significantly with the density of immune T CD3+, CD4+, CD8+, CD45RO+ and FOXP3+ cells, as well as macrophages CD68+ cells in tumors (r values range: 0.22-0.45; P values range: 0.001-0.02). Overall, we did not find significant correlations between CD73 immunostaining and the IHC expression of the immune checkpoints examined. CD73 IHC expression correlated positively with mRNA CD73 gene expression levels in all NSCLCs (r=0.6; P<0.0001), ADCs (r=0.6; P<0.0001), and SqCCs (r=0.49, P<0.0001) histology

      8eea62084ca7e541d918e823422bd82e Conclusion

      We identified that CD73 protein expresses in a subset of resected NSCLCs, being significantly higher in adenocarcinoma histology. In this histology type, CD73 correlates with immune T cells and macrophages infiltration, and notably, with tumor’s EGFR and KRAS mutation. Our data suggest that CD73 is a potential target for NSCLC, particularly for adenocarcinoma histology (Supported by grants CPRIT RP160668 and UT Lung SPORE).

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)

      12:00 - 13:30  |  Author(s): Neda Kalhor

      • Abstract

      Background

      Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

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