Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer

Heath D. Skinner, Uma Giri, Liang P. Yang, Manish Kumar, Ying Liu, Michael D. Story, Curtis R. Pickering, Lauren A. Byers, Michelle D. Williams, Jing Wang, Li Shen, Suk Y. Yoo, You Hong Fan, David P. Molkentine, Beth M. Beadle, Raymond E. Meyn, Jeffrey N. Myers, John V. Heymach

Research output: Contribution to journalArticle

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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 usingimmunohistochemistry. 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 PDL1 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.

Original languageEnglish (US)
Pages (from-to)2713-2722
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number11
DOIs
StatePublished - Jun 1 2017

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Papillomaviridae
Head and Neck Neoplasms
Phosphatidylinositol 3-Kinases
Radiation
Radiotherapy
Cell Line
Tumor-Infiltrating Lymphocytes
Treatment Failure
Proteomics
Cause of Death
Neoplasms
Research Design
Up-Regulation
Multivariate Analysis
Messenger RNA
Carcinoma, squamous cell of head and neck
Proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer. / Skinner, Heath D.; Giri, Uma; Yang, Liang P.; Kumar, Manish; Liu, Ying; Story, Michael D.; Pickering, Curtis R.; Byers, Lauren A.; Williams, Michelle D.; Wang, Jing; Shen, Li; Yoo, Suk Y.; Fan, You Hong; Molkentine, David P.; Beadle, Beth M.; Meyn, Raymond E.; Myers, Jeffrey N.; Heymach, John V.

In: Clinical Cancer Research, Vol. 23, No. 11, 01.06.2017, p. 2713-2722.

Research output: Contribution to journalArticle

Skinner, HD, Giri, U, Yang, LP, Kumar, M, Liu, Y, Story, MD, Pickering, CR, Byers, LA, Williams, MD, Wang, J, Shen, L, Yoo, SY, Fan, YH, Molkentine, DP, Beadle, BM, Meyn, RE, Myers, JN & Heymach, JV 2017, 'Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer', Clinical Cancer Research, vol. 23, no. 11, pp. 2713-2722. https://doi.org/10.1158/1078-0432.CCR-16-2586
Skinner, Heath D. ; Giri, Uma ; Yang, Liang P. ; Kumar, Manish ; Liu, Ying ; Story, Michael D. ; Pickering, Curtis R. ; Byers, Lauren A. ; Williams, Michelle D. ; Wang, Jing ; Shen, Li ; Yoo, Suk Y. ; Fan, You Hong ; Molkentine, David P. ; Beadle, Beth M. ; Meyn, Raymond E. ; Myers, Jeffrey N. ; Heymach, John V. / Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 11. pp. 2713-2722.
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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 usingimmunohistochemistry. 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 PDL1 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.",
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T1 - Integrative analysis identifies a novel AXL-PI3 kinase-PD-L1 signaling axis associated with radiation resistance in head and neck cancer

AU - Skinner, Heath D.

AU - Giri, Uma

AU - Yang, Liang P.

AU - Kumar, Manish

AU - Liu, Ying

AU - Story, Michael D.

AU - Pickering, Curtis R.

AU - Byers, Lauren A.

AU - Williams, Michelle D.

AU - Wang, Jing

AU - Shen, Li

AU - Yoo, Suk Y.

AU - Fan, You Hong

AU - Molkentine, David P.

AU - Beadle, Beth M.

AU - Meyn, Raymond E.

AU - Myers, Jeffrey N.

AU - Heymach, John V.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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 usingimmunohistochemistry. 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 PDL1 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.

AB - 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 usingimmunohistochemistry. 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 PDL1 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.

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