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F. Kosari
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.02 - Anti-Tumor Immunity is a Key Determinant of SCLC Survivorship (ID 5759)
14:30 - 14:40 | Author(s): F. Kosari
- Abstract
- Presentation
Background:
While the majority of small cell lung cancer (SCLC) patients succumb to their disease within a few months, there is a small group of patients who survive for many years after their diagnosis. Factors contributing to the SCLC long-term survivorship remain largely unknown. Herein, we compared tumors from exceptional survivors (EXS) and patients with the expected outcome (EOP) to determine genomic and immunological determinant of SCLC survivorship.
Methods:
In the Mayo Clinic tissue registry, we identified surgical blocks from 12 EXS who survived > 4 years after surgery and 14 EOP who died < 2 years of surgery. These cohorts were created to have no statistical differences in clinical TNM stage, curative versus non-curative intent surgery, age, gender, and smoking status between EXS and EOP. Tumor areas were macro-dissected for gene expression profiling by the Human Transcriptome Array (Affymetrix). Also, tissue sections were stained for key immunological markers, including CD8, CD4, CD3, CD279, FoxP3, CD138, CD20, CD21, CD14, CD68, and also LYZ. Concentrations of immune cells in intra-tumor areas (IE), stroma (ST), and tumor/non-tumor interface (IF) were assessed by an image processing program (Aperio). Staining patterns in each of the three zones in EXS and EOP tumors were compared.
Results:
More than 90% of differentially expressed genes were over-expressed in EXS compared with EOP. Furthermore, over 75% of the known over-expressed genes were either immunoglobulin or MHC related and a majority of the remaining genes were immune function related such as cytokines. We then performed IHC for key immunological markers and found significantly higher concentration of immune cells including CD8 and PD-1 positive cells in the tumor microenvironment, especially at the tumor stromal interface in EXS compared with EOP (p < 0.005 for both markers). Furthermore, the total number of infiltrating immune cells (T-cells, B-cells, Plasma cells, monocytes and macrophages was significantly higher in EXS in the interface region (p < 0.0005).
Conclusion:
Gene expression profiling revealed that anti-tumor immunity is an important factor for SCLC survival. Further studies by IHC suggested the presence of immune cells especially cytotoxic T-cells in the tumor microenvironment and particularly at the tumor-stromal interface to be major contributors to long term survivorship in SCLC. These findings suggest that immunotherapeutic strategies may be effective for patients with SCLC.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-060 - EGFR Mediates Activation of RET in Lung Adenocarcinoma with Neuroendocrine Differentiation Characterized by ASCL1 Expression (ID 5804)
14:30 - 14:30 | Author(s): F. Kosari
- Abstract
Background:
Achaete-scute homolog 1 (ASCL1) is a neuroendocrine transcription factor expressed in 10-20 % of lung adenocarcinomas (AD) with neuroendocrine (NE) differentiation. Previously, we demonstrated that ASCL1 functions as an upstream regulator of the RET oncogene in AD with high ASCL1 expression (A[+]AD). In this study, we examined the potential role of wild type RET in influencing the oncogenic properties of A[+]AD. We also screened for drugs that could selectively target RET signaling and examined the role of the two RET isoform separately.
Methods:
The association of the mRNA expression for the long (RET51) and short (RET9) RET isoforms with overall survival (OS) were assessed in a case-control study of stage-1 A[+]AD patients surgically resected at the Mayo Clinic (1994-2007). Cases and controls were defined as patients who survived < 3.5 years after surgery (n= 29) and > 5 years after surgery (n=38), respectively. mRNA was isolated from FFPE tissue and analyzed by a nanostring assay. Associations of each isoform mRNA with the OS was determined by the area under the receiver operative characteristics (AUC). For drug screening, HCC1833 lung AD cells with endogenously high expression of ASCL1 were stably transfected with either empty vector or an ASCL1-shRNA. Differential sensitivities of tyrosine kinase inhibitors (TKIs) in the pair of syngeneic cell lines were measured by Cell-Titer Glo (Promega). Interactions between EGFR and RET was examined by co-immunoprecipitation.
Results:
Expression of RET51 mRNA was associated with poor OS (p=0.005, AUC 0.71). We detected modestly increased sensitivity to sunitinib and vandetanib in A[+]AD compared with A[-]AD cells. However, the EGFR inhibitors gefitinib and the dual EGFR and HER2 inhibitor lapatinib resulted in ≥ 10 fold higher cytotoxicity in A[+]AD cells than in A[-]AD cells. Subsequent experiments demonstrated that EGF stimulation of EGFR mediates the phosphorylation of RET in multiple A[+]AD cells. RET and EGFR were found to interact only in presence of EGF and predominantly through the long RET isoform (RET51).
Conclusion:
Herein we demonstrate that wild type EGFR predominantly interacts with the long isoform of RET (RET51) in A[+]AD cells. In the presence of EGF this results in activation of RET. High RET51 is associated with worse OS. Furthermore, compared to A[-]AD cells, A[+]AD cells appear to be more sensitivity to EGFR inhibitors. In summary, our results suggest that A[+]AD patients may benefit from treatment with EGFR inhibitors even in the absence of an EGFR mutation.
