Strong Link Found Between PD-L1 Expression, Radiation Resistance in HPV-Negative HNSCC

A strong association was found between high PD-L1 expression and local failure following radiotherapy in HPV-negative head and neck squamous cell carcinomas.

Heath D. Skinner, MD, PhD

Heath D. Skinner, MD, PhD

A strong association was found between high PD-L1 expression and local failure following radiotherapy in HPV-negative head and neck squamous cell carcinomas (HNSCC), according to results recently published online inClinical Cancer Research.

“There was a pretty strong and striking association between tumor PD-L1 expression and failure following radiation,” lead author Heath D. Skinner, MD, PhD, assistant professor in the department of radiation oncology at MD Anderson Cancer Center, said in an interview withTargeted Oncology. “Moreover, we also found that AXL and PI3 kinase signaling appeared to be at least partially responsible for the high levels of PD-L1. If you inhibit AXL or PI3 kinase in vitro, that decreased PD-L1 expression.”

Skinner and colleagues initiated the study aiming to identify novel markers of resistance to radiation treatment and explore upstream signaling to PD-L1 in HPV-negative HNSCC.

To identify pathways associated with radioresistance, investigators repeatedly exposed an HPV-negative HNSCC cell line to doses of 2 Gy radiation over a 4-week period. The result was a cell line they called FADU RR that was significantly more radioresistant than the FADU parent line.

Using reverse phase protein array (RPPA) to compare the 2 lines, Skinner et al observed AXL and p-AXL, markers of PI3K/AKT/mTOR pathway activation, and PD-L1 among the top proteins upregulated in FADU RR cells compared with parental line. The false discovery rate was 0.1.

The association between AXL-PI3 kinase signaling and PD-L1 expression was subsequently confirmed in cohorts of 68 and 97 patients with locally advanced HPV-negative HNSCC treated with surgery and postoperative radiotherapy.

When investigators performed a univariate analysis of locoregional recurrence (LRR) following radiation for each protein on RPPA, they found that PD-L1 was 1 of the most significant proteins associated with LRR (P= .0034). Further analysis, including clinical variables, showed that PD-L1 expression remained significantly associated was LRR (P= 3.2 x 10-4). Three-year LRR rate was 60% in patients with tumors expressing high levels of PD-L1 compared with 20% in the low PD-L1 group (P= .01).

PD-L1 expression was significantly associated with disease-specific survival (P= .04), but there was no association seen with distant metastasis (P= .8).

Investigators found PD-L1 to be a strong predictor for LRR. Using a tissue microarray of tumor samples collected from patients with HPV-negative HNSCC treated with surgery and postoperative radiotherapy, multivariate analysis showed that only PD-L1 expression (P= .021) and nodal stage (P= .011) were associated with LRR. The 3-year LRR rate was 50% in the high PD-L1 group compared with 20% in the low PD-L1 group (P= 9 x 10-4).

PD-L1 was associated with LRR in either a p53 wildtype (P= .002) or mutant context and (P= .014). Investigators added that high PD-L1 expression was slightly less common in p53 wild-type tumors compared with p53 mutant tumors (20% vs 35%), but PD-L1 expression overall was similar in both p53 wild-type and mutant tumors.

Investigators then stratified patients by CD8-positive (≥10 cells) and/or tumor PD-L1—positive (≥30% of tumor-positive) status based on IHC. PD-L1 remained predictive of outcome regardless of CD8-positive immune infiltrate, but patients who were CD8-positive/PD-L1–negative (n = 12) had better outcomes than other patients. This group had no local failures (P= 5 x 10-4) and no disease-related deaths (4 x 10-4).

“We have a validated and clinically usable marker of patients who are going to do worse following radiation in HPV-negative head and neck cancer,” Skinner said. “I do believe that if you can inhibit PD-L1 in this setting, you can improve overall survival in this cohort of patients. It’s nice because PD-L1 antibody is currently in use in the clinic. You can test these patients upfront, and if they have high levels of expression of PD-L1, an excellent trial would be to combine PD-L1 targeted therapy with radiation.

“Immuno-oncology has taken the field by storm. I think there is an enormous role for radiation to play in that field.”


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 [published online May 11, 2017].Clin Cancer Res.10.1158/1078-0432.CCR-16-2586.

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