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Abstract

Purpose: 

The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach.

Experimental Design:

We utilized human papilloma virus (HPV)-negative cell lines rendered radiation-resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.

Results:

RR cell lines exhibited upregulation of several proteins compared with controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA 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. Indeed, 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 = 0.01, 1.9 × 10-3, and 9 × 10-4, respectively). This finding remained significant on multivariate analysis in all groups. Additionally, patients with PD-L1 low/CD8+ tumor-infiltrating lymphocytes high had no local failure or death due to disease (P = 5 × 10-4 and P = 4 × 10-4, respectively).

Conclusions: 

Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance.

Translational Relevance

Locoregional failure is the primary cause of death in head and neck cancer (HNSCC). Treatment of locally advanced HNSCC is typically composed of radiation in combination with either surgical resection and/or cytotoxic chemotherapy. Although human papilloma virus (HPV)-positive HNSCC is sensitive to radiation, HPV-negative tumors are comparatively resistant to this treatment. Thus, understanding potential, clinically targetable drivers of radioresistance in HPV-negative tumors is necessary to improve survival.

In the current study, we identified PD-L1 as significantly associated with locoregional failure following radiation in multiple cohorts of HPV-negative tumors. Interestingly, PD-L1 expression appears to be at least partly driven by Axl–PI3 kinase signaling. These data provide further support to incorporate agents that target PD-1/PD-L1 in combination with radiation in this patient population as well as provide potential selection criteria for these trials. Moreover, our data suggest that, in addition to direct antitumor effects, targeting either Axl or PI3 kinase may provide a benefit in regard to tumor immune response.​

Author information​

Skinner HD1, Giri U2, Yang LP3, Kumar M3, Liu Y3, Story MD4, Pickering CR5, Byers LA2, Williams MD6, Wang J7, Shen L7, Yoo SY7, Fan YH7, Molkentine DP3, Beadle BM8, Meyn RE3, Myers JN5, Heymach JV2.

1 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. hskinner@mdanderson.org.

2 Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

3 Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4 Simmons Comprehensive Cancer Center, Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas.

5 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

7 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

8 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.