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A. Hata
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MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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MINI02.02 - Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases (ID 1519)
10:50 - 10:55 | Author(s): A. Hata
- Abstract
Background:
Inhibition of PD-L1 can lead to reactivation of tumor immunity and assist in cancer therapy. PD-L1 expression in tumor cells has been reported to correlate with clinicopathological parameters and prognosis in a variety of cancers including lung adenocarcinomas (ADC). However, it has not been well studied whether PD-L1 expression is altered along with tumor progression. In addition, little is known about the role of PD-L1 expression in predicting response to chemotherapy in ADC. Thus, we sought to compare PD-L1 expression in the main tumor and lymph node metastases of stage II and III ADC, and correlate PD-L1 expression with survival in patients who underwent adjuvant chemotherapy.
Methods:
The study cohort consisted of 109 ADC who underwent curative resection without neoadjuvant therapy and were diagnosed to have stage II or III disease. Of those, 60 cases received platinum-based adjuvant therapy and were followed at our institution. Immunohistochemistry for PD-L1 (E1L3N, 1:200, CST) was performed on sections of the primary tumor and/or metastatic lymph nodes and the primary tumor sections were also stained with CD8 (4B11, RTU, Leica Bond). Membranous staining of any intensity present in 5% or more of the tumor cells was deemed positive for PD-L1 expression. CD8+ tumor infiltrating lymphocytes (TILs) were evaluated using a 4-tier grading system (0-3). The PD-L1 expression in the primary tumor was correlated with that in lymph node metastases as well as clinicopathological parameters, including CD8+ TILs, and recurrence free survival (RFS).
Results:
Of the 109 cases, 53 (48.6 %) exhibited PD-L1 expression in the primary tumor, which was significantly associated with smaller tumor size, lower pT stage, nodal disease, solid-predominant pattern, the presence of tumor islands, necrosis and lymphovascular invasion, and increased CD8+ TILs (grade 2-3). Upon multivariate analysis, only increased CD8+ TILs remained significant (p=0.039). As for the primary – lymph node correlation, PD-L1 expression was seen in 57.6% of 59 N1 nodes, 53.1% of 32 N2 nodes, and 100% of one N3 node available for evaluation. The PD-L1 expression status was the same between the primary tumor and nodal metastases in the majority (76.3 % of N1 nodes, and 75.0% of N2; p<0.001 and p=0.005, respectively), and the upregulation of PD-L1 expression (positive expression was present in nodal metastasis with negative primary) was seen in only small fractions of the cohort (6.8% of N1 nodes and 9.3% of L2 nodes). Interestingly, PD-L1 expression in the primary tumor was associated with longer RFS in patients who underwent platinum-based adjuvant therapy (mean 84 months vs. 41 months in PD-L1 negative patients, p=0.016), but not in those without adjuvant therapy.
Conclusion:
PD-L1 expression in the primary tumor was associated with prominent CD8+ TILs as well as several adverse clinicopathological parameters including nodal disease, but PD-L1 expression in the nodal metastasis was similar to that in the primary tumor in the majority of cases. Although the evaluation was limited due to a small size of the cohort, PD-L1 expression in the primary tumor appears to be predictive of response to platinum-based adjuvant therapy.
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ORAL 13 - Immunotherapy Biomarkers (ID 104)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Kim, D. Grunenwald
- Coordinates: 9/07/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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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 - 16:56 | Author(s): A. Hata
- Abstract
- Presentation
Background:
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.
Methods:
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).
Results:
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.
Conclusion:
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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