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Montse Sanchez-Cespedes
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MA 15 - Lung Cancer Biology II (ID 670)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Biology/Pathology
- Presentations: 1
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MA 15.05 - Discussant - MA 15.01, MA 15.02, MA 15.03, MA 15.04 (ID 10774)
16:05 - 16:20 | Presenting Author(s): Montse Sanchez-Cespedes
- Abstract
- Presentation
Abstract not provided
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P2.08 - Locally Advanced Nsclc (ID 709)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.08-006 - Immunological Biomarkers Characterization in Locally Advanced Non-Small Cell Lung Cancer Treated with Concurrent Chemo-Radiotherapy (ID 9584)
09:30 - 09:30 | Author(s): Montse Sanchez-Cespedes
- Abstract
Background:
The immune microenvironment of locally advanced non-small cell lung cancer (NSCLC) has not been systematically studied. Our aim was to determine the prognostic value of immunological biomarkers expression in a cohort of patients (pts) in this clinical setting.
Method:
We retrospectively reviewed 46 bronchial biopsies from locally advanced NSCLC. Pts were treated between 2010 and 2014 with concurrent chemo-radiotherapy (cCRT) at the Catalan Institute of Oncology. The following immunological markers were assessed by immunohistochemistry: PD-L1, ≥5% membrane expression on tumor cells was considered positive (+); HLA-Class I expression was classified into 0,1+,2+ according to membrane intensity; CD8+ tumor infiltrating lymphocytes (CD8 TILs) classified into low ≤5% or high >5% intratumoral infiltration. Chi-square test for assessing correlation and survival analysis by Kaplan-Meier method were used.
Result:
From 46 pts: Median age was 65 (43-81); gender: male 94%, female 6%; ECOG≤1 96%; smoking status: current 67%, former 30%, never 3%; histology: squamous cell carcinoma (SCC) 63%, adenocarcinoma (ADC) 24%, NSCLC (NOS+large cell) 13%; cN0-1 30%, cN2 57%, cN3 13%. Platinum doublet CT: Cisplatin 57%, Carboplatin 43%. PD-L1 was positive in 38% of cases and was positively correlated with HLA-I expression (p= 0.015) and CD8-TILs (p= 0.008). No correlations between PD-L1/CD8 TILs status and G3-4 radio-induced toxicities (pneumonitis, esophagitis) were found. At a median follow-up of 48 months (m), 53% of pts had relapsed. According to immune phenotype, median overall survival (mOS) was 20m (PD-L1 +, CD8 high; n=10) vs 17 m (PDL1 negative, CD8 low; n=19) vs not reached (PD-L1 negative, CD8 high; n=5) (p=0.23). Considering CD8 TILs, mOS in high CD8 (n=15) was 35m vs 18 m in low CD8 (n=26) (p=0.22).
Conclusion:
PD-L1, HLA-I and TILs CD8 expression was positively correlated. The potential role of TILs CD8+ as a prognostic biomarker in this cohort of pts that comprised mostly SCC histology, is promising. These results should be investigated in a larger cohort.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-086 - MGA Suppresses the MYC Pathway in Lung Adeocarcinoma (ID 8022)
09:30 - 09:30 | Author(s): Montse Sanchez-Cespedes
- Abstract
Background:
Recent exome-sequencing efforts have revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated (~8%) in lung adenocarcinomas. Most MGA mutations are loss-of-function, suggesting that MGA may act as a tumor suppressor. MGA mutations are mutually exclusive to MYC gene amplification, suggesting the involvement of MGA in the MYC pathway. Here, we aimed to characterize both the cellular and molecular role of MGA in lung adenocarcinoma, with a focus on studying its role in modulating the MYC pathway.
Method:
Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analysis were used to identify MYC and MGA DNA binding sites and binding motifs. Inmunoprecipitation assays and mass spectrometry were used to elucidate MGA gene repression mechanism. Cell competition assay was performed to measure cell proliferation with and without MGA overexpression. Finally, electrophoretic mobility shift assays (EMSA) were used to functionally evaluate MGA DNA binding ability to E-boxes when missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA occur.
Result:
We found that ectopic expression of wild-type MGA represses the cellular growth of lung adenocarcinoma cell lines. Chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-sequencing (RNA-seq) analyses revealed that MGA recognizes the same DNA binding motif as MYC, shares a large proportion of genomic DNA binding sites with MYC, and represses expression of MYC target genes. Immunoprecipitation assays in combination with mass spectrometry analysis reported that MGA interacts with several gene repressing proteins and complexes, such as the Polycomb repressive complex 1 (PRC1), histone deacetylases HDAC1/2, and the E2F6 transcriptional repressor, suggesting a potential mechanism by which MGA represses its target genes. In addition, we analyzed the mutation profile of MGA on a pan-cancer scale, revealing recurrent missense mutations in the basic-Helix-Loop-Helix (bHLH) domain of MGA in other cancer types such as colorectal and endometrial carcinomas. Electrophoretic mobility shift assays (EMSA) showed that these missense mutations impair the DNA binding ability of MGA, suggesting that these missense mutations, in addition to truncation mutations, disrupt the function of MGA in cancer cells.
Conclusion:
In summary, our results suggest that MGA plays a tumor suppressor role by binding to and repressing MYC target genes, thus expanding our current knowledge of genomic mechanisms for MYC pathway activation in cancer.
