Heath D. Skinner, MD, PhD
According to a study by Heath D. Skinner, MD, PhD, of The University of Texas MD Anderson Cancer Center, and colleagues, the primary cause of death in patients with head and neck squamous cell carcinoma is local treatment failure. Although human papillomavirus (HPV)-positive head and neck squamous cell carcinoma is sensitive to radiation, HPV-negative tumors are comparatively resistant to the treatment. In their study, they sought to identify and validate potentially targetable biomarkers to improve survival in patients with HPV-negative head and neck squamous cell carcinoma. Their findings identified programmed cell death ligand 1 (PD-L1) as significantly associated with locoregional failure following radiation in HPV-negative tumors. The findings support incorporating immune checkpoint blockade and radiation and potentially utilizing Axl or PI3 kinase blockade to affect both tumor radiosensitization and immune response. The study was published in Clinical Cancer Research.
The researchers utilized HPV-negative cell lines rendered radiation-resistant via repeated exposure to radiation, a panel of HPV-negative head and neck squamous cell carcinoma cell lines, and three cohorts of HPV-negative head and neck squamous cell carcinoma tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.
The researchers found that the radiation-resistant cell lines exhibited upregulation of several proteins compared with the controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. In addition, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to reverse-phase protein array and mRNA expression analysis, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy.
This finding was confirmed examining a third cohort using immunohistochemistry. The investigators found that tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70%, and 50%, compared with 20%, 25%, and 20% in the PD-L1–low expression group (P = .01, 1.9 × 10-3, and 9 × 10-4, respectively). This finding remained significant on multivariate analysis in all groups. Also, patients with PD-L1 low/CD8-positive tumor-infiltrating lymphocytes high had no local failure or death due to increase (P = 5 × 10-4 and P = 4 × 10-4, respectively).
“In the current study, we identified and validated PD-L1 as a significant biomarker of treatment failure in HPV-negative head and neck squamous cell carcinoma following radiotherapy using both screening approaches as well as targeted [immunohistochemistry]. This phenomenon appears to be linked to Axl/PI3 kinase signaling within the tumor. These findings provide a strong rationale for the combination of immune checkpoint blockade and radiation in this setting, as well as potentially utilizing Axl or PI3 kinase blockade to affect both tumor radiosensitization and immune response,” concluded the study authors.
Skinner HD, et al: Clin Cancer Res 23:2713-2722, 2017. ■