397PD - KRAS mutation-induced upregulation of PD-L1 mediates immune escape in lung adenocarcinoma

Date 19 December 2016
Event ESMO Asia 2016 Congress
Session Immunotherapy of cancer
Topics Cancer Immunology and Immunotherapy
Lung and other Thoracic Tumours
Translational Research
Presenter Shaodong Hong
Citation Annals of Oncology (2016) 27 (suppl_9): ix123-ix125. 10.1093/annonc/mdw588
Authors S. Hong1, N. Chen2, W. Fang2, J. Zhan2, L. Zhang2
  • 1Medical Oncology, Cancer Centre Sun Yat-Sen University, 510060 - Guangzhou/CN
  • 2Medical Oncology, 5th Affiliated Hospital, Sun Yat-sen University, 519000 - Zhuhai/CN

Abstract

Background

Programmed death-ligand 1 (PD-L1) expression is associated with EGFR mutation and EML4-ALK rearrangement. Whether PD-L1 is regulated by other driver mutations like KRAS in lung adenocarcinoma and what is the molecular mechanism remain largely unknown.

Methods

In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by KRAS mutation. Relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by KRAS mutation and immune reactivation by ERK inhibitor and/or PD-1 blocking in tumor cells and T cells co-culture system.

Results

We found that PD-L1 expression was correlated with KRAS mutation in the cell lines and human tissue of lung adenocarcinoma. PD-L1 was up-regulated by KRAS mutation through p-ERK but not p-AKT signaling.We also found that KRAS-mediated up-regulation of PD-L1 induced the apoptosis of CD3-positive T cells which was reversed by pembrolizumab or ERK-specific inhibitor. Blocking PD-1 by anti-PD-1 antibody or PD-L1 by ERK inhibitor could re-activate the anti-tumor immunity of T cells and decrease the survival rates of KRAS-mutant NSCLC cells in co-culture system in vitro. However, we did not observe the synergistic effect of pembrolizumab and ERK inhibitor together on killing of tumor cells in co-culture system.

Conclusions

Our study demonstrates that KRAS mutation induces PD-L1 expression through p-ERK signaling in lung adenocarcinoma. Therapy targeting PD-1/PD-L1 axis provides a promising treatment option for KRAS-mutant lung adenocarcinoma.

Clinical trial indentification

NA

Legal entity responsible for the study

Sun Yat-sen University Cancer Center

Funding

Sun Yat-sen University Cancer Center

Disclosure

All authors have declared no conflicts of interest.