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E. Franks
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.12 - Oncogenic Drivers Induce Production of CCL5 to Recruit Regulatory T-Cells Early in Lung Cancer Progression (ID 10289)
17:00 - 17:05 | Author(s): E. Franks
- Abstract
- Presentation
Background:
Lung cancer development is driven by the expression of mutant oncogenes, with EGFR and KRAS the most frequent in lung adenocarcinoma. However, these mutations alone are not sufficient for tumorigenesis suggesting additional factors influence tumour development and progression, including the balance of anti-tumour immune effector cells and pro-tumorigenic immune suppressor cells. Tumour cells can evade immune surveillance by producing cytokines to recruit immune modulatory cells that promote an immune suppressive environment, such as regulatory T cells (Tregs). We hypothesized that oncogene signaling regulates the production of cytokines by tumour cells in order to recruit immune suppressive cells and promote lung tumour development.
Method:
We used CIBERSORT to quantify 22 immune cell types in over 300 human lung adenocarcinoma and 100 matched normal lung tissues, and validated findings with immunohistochemistry. Cells expressing doxycycline inducible EGFR[L858R] and KRAS[G12V]were analyzed for cytokine production using a multiplex assay (LUMINEX). EGFR (Afatinib) and MEK (Trametinib) inhibitors were used in lung cancer cell lines harbouring EGFR or KRAS mutations and cytokine production was quantified using ELISA. Conditioned media from EGFR[L858R] and KRAS[G12V] expressing cells were used in a trans-well assay to determine if secreted cytokines could induce Treg migration. Transgenic mouse models of lung adenocarcinoma and bronchoalveolar lavage (BAL) from patients with and without lung cancer were used to assess CCL5 and Tregs in vivo.
Result:
Treg cells were significantly enriched in lung tumours and not normal tissue. CCL5 production is increased rapidly upon oncogene induction and subsequent transformation of normal cells and is dependent on sustained ERK signaling for continued expression. Conditioned medium from EGFR[L858R] expressing cells increased Treg migration, which was mitigated by an anti-CCL5 antibody. Transgenic mice expressing EGFR[L858R ]or KRAS[G12D] in the lung epithelium recruited Tregs to the lung upon tumor induction. Assessment of CCL5 in BAL from patients with and without lung cancer is currently in progress.
Conclusion:
Oncogene driven ERK signaling may regulate expression of CCL5 from lung tumour cells, and oncogene induced CCL5 production stimulates Treg migration ex vivo. These data suggest CCL5-mediated Treg recruitment to lung tumours may occur in early stages of lung tumour development and that targeted inhibition of CCL5 or ERK signaling may represent therapeutic strategies to block recruitment of immunosuppressive Tregs by lung tumours.
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