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B. Sepesi



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    OA 13 - Immuno-Biology (ID 677)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Immunology and Immunotherapy
    • Presentations: 1
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      OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)

      11:00 - 12:30  |  Author(s): B. Sepesi

      • Abstract
      • Presentation
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.

      Method:
      We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.

      Result:
      Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.

      Conclusion:
      These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.

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    P2.02 - Biology/Pathology (ID 616)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P2.02-041 - Update on Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer (ICON Project) (ID 10156)

      09:30 - 16:00  |  Author(s): B. Sepesi

      • Abstract
      • Slides

      Background:
      Given the rapidly changing therapeutic landscape for non-small cell lung cancer (NSCLC), a thorough understanding of the tumor immune environment is critical to the appropriate selection of patients and testing of immuno-oncology agents. We established a project aimed at defining the comprehensive and integrated immunogenomic landscape in NSCLC, including immune, genomic and clinical data from 100 surgically resected lung cancers.

      Method:
      Tissue samples were collected at the time of surgery, and blood samples before and after surgery up to 1-year. Tissue samples were subjected to tumor infiltrating lymphocyte (TIL) isolation and expansion; generation of PDX models,WES and in-silico neoantigen prediction, RNA sequencing, RPPA, CyTOF, T cell receptor sequencing, and multiplex immunofluorescence evaluation of immune cells and markers. Blood samples were processed for cfDNA, microRNA, and cytokine profiling.

      Result:
      93 out of 131 enrolled patients with median age 67 years contributed samples to ICON; 44% males, 80% former smokers, 12% never smokers. Majority had adenocarcinoma (60%) and 26% SCC. 37 (40%) had stage I, 29 (31%) stage II, and 20 (22%) stage III disease; 14 patients received neoadjuvant chemotherapy. Median tumor size was 4.0cm and 79 (85%) underwent R0 and 9 (10%) R1 resection. TIL expansion was 68% successful. Phenotypic and functional analysis of TIL is ongoing. Preliminary analysis show suppression of intratumoral CD8[+] cells with low perforin levels and high CD8[+]PD1 levels as compared to normal tissue; however tumor CD8[+]CD28 co-stimulatory molecule expression was high. PDX success rate is 35%. IHC analyses show higher CD8[+]PD1, CD3, CD8[+]BTLA expression in SCC than in adenocarcinoma or normal tissue. WES and RNA sequencing show that median mutation burden is 9.3/MB in adenocarcinomas and 11.2/MB in SCC. Other immunogenomic analyses are in process.

      Conclusion:
      The ICON is an ambitious multi-team project designed to integrate multiple levels of tumor related data. Preliminary analysis demonstrates the project to be feasible, with a high rate of prospective sample acquisition. Tumor profiles from ICON will serve as a reference for upcoming neoadjuvant single and dual checkpoint immunotherapy trials. ICON Team: A. Weissferdt, A. Vaporciyan, A. Futreal, T. Karpinets, C. Yee, C. Haymaker, L. Federico, M.-A. Forget, G. Lizee, A. Talukder, J. Roszik, H. Tran, M. Vasquez, E. Prado, C. Behrens, E. Parra, J. Rodriguez-Canales, J. Fujimoto, L. Vence, J. Roth, I. Meraz, E. Roarty, L. Lacerda, L. Byers, S. Swisher, W. William Jr., P. Sharma, J. Allison, B. Fang, H. Wagner, E. Bogatenkova, I. Wistuba, J. Heymach and C. Bernatchez

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