Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors

By Esra A. Akbay, S. Koyama, J. Carretero, Abigail Altabef, J. Tchaicha, C. L. Christensen, O. Mikse, A. Cherniack, Ellen M. Beauchamp, Trevor J. Pugh and 17 more. Cancer Discovery, 2013

1,183 citations recorded by the source corpus.

The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/0ba2bcbe04a14ef9c70e7f11b94fb035b135d453

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. G. Dranoff
2. J. Engelman
3. Razelle Kurzrock
4. S. Patel
5. M. Hung
6. G. Freeman
7. J. Hsu
8. Chia‐Wei Li

In Pulmonary and Respiratory Medicine

1. J. Engelman
2. L. Sequist
3. P. Jänne
4. Carlos L. Arteaga
5. Jin-Yuan Shih

Citations in the corpus

• EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective Analysis (2016, background): “Several early clinical reports suggested that EGFR mutations and ALK rearrangements are associated with PD-L1 overexpression (21, 22), with PD-L1 staining in up to 71.”
• Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints (2016, methodology): “We previously reported that a fully immunocompetent mouse model of lung cancer driven by expression of mutated EGFR demonstrates responsiveness to PD-1 blockade associated with augmentation of an anti-tumour T-cell response 17 .”
• Management of acquired resistance to EGFR TKI–targeted therapy in advanced non-small cell lung cancer (2018, neutral): “In vitro, EGFR-mutant lung cancer cells inhibited antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function [120].”
• Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. (2016, background): “This is in agreement with a report demonstrating PD-1 blockade reduced tumor burden in mouse models of mutant EGFR- but not KRASdriven lung cancer (16).”
• Upregulation of PD-L1 by EGFR Activation Mediates the Immune Escape in EGFR-Driven NSCLC: Implication for Optional Immune Targeted Therapy for NSCLC Patients with EGFR Mutation (2015, background): “over-expression of mutant EGFR but not K-ras could increase the level of PD-L1 mRNA in Beas-2B cells.(15) This shows that PD-L1 upregulation is induced by EGFR activation and not simply by oncogenic stress.”
• Mechanisms controlling PD-L1 expression in cancer (2019, background): “Besides MYC and ALK, the HIF1/2α, NF-κB, MAPK, PTEN/PI3K and EGFR oncogenic pathways can also boost PD-L1 mRNA expression when they are mutated or hyperactivated (Akbay et al., 2013; Atefi et al., 2014; Barsoum et al., 2014; Jiang et al., 2013; Peng et al., 2015; Xu et al., 2014).”
• Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “reported a correlation between activation of the epidermal growth factor receptor (EGFR) pathway and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTLA-4, and inflammatory cytokines (Akbay et al., 2013).”
• CDK4/6 Inhibition Augments Anti-Tumor Immunity by Enhancing T Cell Activation (2017, background): “The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”