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Lorenzo Federico



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)

      13:35 - 13:40  |  Author(s): Lorenzo Federico

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • 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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      P1.03-12 - PD-L1 Expression is Predominant in CD68+ Tumor-Associated Macrophages in Stage I-III Non-Small Cell Lung Cancers (ID 13340)

      16:45 - 18:00  |  Author(s): Lorenzo Federico

      • Abstract
      • Slides

      Background

      PD-L1 tumor expression is a leading biomarker in metastatic non-small lung cancer (NSCLC). Its role and expression in surgically resectable lung cancers is not yet defined. The association between PD-L1 expression on tumor and CD68+ tumor-associated macrophages (TAMs) and the inflammatory cells within the tumor microenvironment continues to be studied. We analyzed 97 surgically resected lung cancers utilizing immunofluorescence profiling and flow cytometry (n=47) with the aim of defining PD-L1 expression and its association with tumor inflammatory cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplex immunofluorescence profiling of lung cancers was performed with the focus on malignant cells (MC), MC PD-L1%, CD3+, CD8+, PD-1+ cells, CD68+, CD68+ PD-L1%, and CD20+ cells. Data on cell populations were expressed as the number of cells per mm2, PD-L1 expression as percentage. Flow cytometry was performed on freshly disaggregated tumor samples. The associations of cell populations with clinical and pathologic characteristics were assessed using Spearman's rank correlation coefficient and Wilcoxon rank-sum test.

      4c3880bb027f159e801041b1021e88e8 Result

      97 patients, 55 (57%) female and 42 (43%) male, with median tumor size 4.0 cm underwent surgical resection for pathologic stage I (N=39), stage II (N=34), and stage III (N=24) NSCLC. 85 (88%) were former smokers, 12 (12%) never smokers. 62 (65%) had adenocarcinoma, 25 (25%) squamous cell carcinoma, 10 (10%) other histology. Neoadjuvant chemotherapy was administered in 16 (16%) patients. R0 resection was achieved in 89 (92%) patients. At the median follow-up duration of 16 months, 18 patients experienced recurrence.

      CD68+ cells were less abundant than MC within tumor environment (median 120 cell/mm2 vs 4699, p<0.0001). However, PD-L1% expression was significantly higher on CD68+ vs MC within the tumor (median 33% vs 0.02%, p<0.0001); this was true for all stages. CD68+ PD-L1% in SCC was higher compared to adenocarcinoma (median 55% vs 30%, p=0.26). Induction chemotherapy increased CD68+ PD-L1% (median 31% no chemo vs 58%, p=0.05) without affecting the proportion of effector CD8+ TIL expressing its receptor, PD-1 (p=0.757). Tumors with > median CD68+ PD-L1% expression were associated with higher CD3+ (p=0.006), CD8+ (p=0.06), and CD68+ (p=0.004) cell numbers within the tumor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In early NSCLC PD-L1% expression appears to be predominant in CD68+ TAMs rather than in malignant cells. Higher than median PD-L1% expression on CD68+ is associated with increased in CD3+ and CD8+ T cells. Further studies are required to understand the role of CD68+PD-L1 cells within tumor microenvironment, the influence of neoadjuvant chemotherapy or immunotherapy regimens on these cells, and their effect on outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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