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V. Morales-Oyarvide

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    ORAL 13 - Immunotherapy Biomarkers (ID 104)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL13.01 - PD-L1 Expression in Lung Adenocarcinomas Correlates with KRAS Mutations and Th1/Cytotoxic T Lymphocyte Microenvironment (ID 2496)

      16:45 - 18:15  |  Author(s): V. Morales-Oyarvide

      • Abstract
      • Presentation
      • Slides

      The interaction of PD-1, with its ligand, PD-L1 induces apoptosis of T cells and inhibits cytokine production, allowing tumor cells to bypass immune surveillance. PD-L1 expression on tumor cells can be upregulated via interferon gamma that is secreted by CD8+ cytotoxic T lymphocytes (CTLs) and/or Th1 pathway activation, counterbalancing the Th1/CTL microenvironment. Blockade of the PD-1/PD-L1 immune checkpoint in solid tumors has resulted in durable responses in early phase clinical trials. Moreover, protein expression of PD-L1 by immunohistochemistry (IHC) reportedly predicts patient response to anti-PD-1/PD-L1 therapies. Multiple studies have reported associations of PD-L1 expression with clinicopathological variables in lung adenocarcinomas (ADC), but such studies have produced conflicting results, possibly due to use of different antibody clones and cutoffs and possibly different ethnicities of the cohort. Thus, we correlated PD-L1 expression with clinicopathological and molecular profiles including subtypes of tumor infiltrating lymphocytes (TILs) in a large lung ADC cohort using a cut-off commonly used in clinical trials.

      PD-L1 (E1L3N, 1:200, CST), CD8 (4B11, RTU, Leica Bond), T-bet (Th1 transcription factor, D6N8B, 1:100, CST), and GATA3 (Th2 transcription factor, L50-823, 1:250, Biocare) IHC were performed on tissue microarrays constructed of 242 resected lung ADC. All cases underwent detailed histological analysis and a subset (n=128) of cases underwent clinical molecular testing. Membranous expression (regardless of intensity) in 5% or more tumor cells was deemed positive for PD-L1 expression. CD8+, T-bet+ and GATA3+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3).

      Our study cohort consisted of 242 patients with a pathologic stage of 0 in 1 case, I in 188, II in 37, III in 9, and IV in 7. Among those, 38 (15.7%) exhibited PD-L1 expression which was significantly associated with smoking history (p=0.008), large tumor size (p=0.007), solid predominant pattern (p<0.001), high nuclear grade (grade 3, p<0.001), vascular invasion (p=0.012), increased T-bet+ TILs (grade 2, p<0.001) and CD8+ TILs (grade 2, p<0.001), and KRAS mutations (p=0.001). High nuclear grade (p=0.011), KRAS mutations (p=0.004), and increased CD8+ TILs (p=0.005) remained significant predictors of PD-L1 expression in multivariate analysis, while advanced stage (II or higher vs. I, p=0.056) showed a trend towards PD-L1 expression. There was no difference in the 5-year progression free survival (PFS) between the PD-L1 positive and negative patients. In contrast, increased CD8+ TILs showed a borderline significance with favorable outcome (p=0.082), with the 5-year PFS being 87% for the CD8 positive group and 68% for the CD8 negative group, but neither PD-L1 nor CD8+ TILs was a significant predictor of survival by the cox proportional-hazards regression model.

      PD-L1 expression in ADC significantly correlates with KRAS mutations and several clinicopathological signatures of KRAS-mutants, including significant smoking history. The latter may have resulted in development of multiple passenger mutations that serve as neoantigens promoting the Th1/CTL microenvironment. These results suggest that blockade of the PD-1/PD-L1 axis may be a promising treatment strategy to reinstitute the Th1/CTL microenvironment for patients with KRAS-mutated ADC, in which there are currently no available treatment options.

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