PD-L1 tumor expression is modulated by Axl and PI3K signaling, and may be a biomarker of radiation response among patients with HPV-negative head and neck squamous cell carcinoma (HNSCC), according to a study published in Clinical Cancer Research.1

Though it is believed that a functioning immune response is needed for optimal response to radiation, the role of this response is not yet understood. This study investigated potential mechanisms associated with immune response and loss of response to radiotherapy.

Radiation resistance was induced in HPV-negative HNSCC cell lines by repeated radiation exposure. Protein expression of Axl, phosphorylated-Axl, PD-L1, and markers of the PI3K/AKT/mTOR pathway were increased in the radiation-resistant cells, but not the parent cell line, which was not radiation resistant.

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The radiation-resistant cell lines also showed a correlation between Axl and PD-L1 expression. Inhibition of Axl or PI3K with a chemical agent or siRNA resulted in decreased PD-L1 expression compared with vehicle control.

The study also collected tumor samples from 3 cohorts of patients with HPV-negative HNSCC who had undergone radiotherapy; 2 of the cohorts included 68 and 97 patients with locally advanced disease, and the third cohort was from The Cancer Genome Atlas.

The investigators also found a correlation between Axl and PD-L1 expression among these tumor samples.

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A tissue array of the tumor samples demonstrated a significant association between locoregional recurrence (LRR) and PD-L1 expression (P = .021). Three-year LRR rates were significantly higher among patients with high PD-L1 expression (50%) compared with low PD-L1 expression (20%; P = .0009).


  1. Skinner HD, Giri U, Yang LP, et al. Integrative analysis identifies a novel AXL-PI3 kinase–PD-L1 signaling axis associated with radiation resistance in head and neck cancer. Clin Cancer Res. 2017 May 5. doi: 10.1158/1078-0432.CCR-16-2586 [Epub ahead of print]