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1
Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells
in head and neck cancer
Sri Krishna*1,2, Peaches Ulrich1,3, Eric Wilson1, Falguni Parikh6, Pooja Narang3,, Shanshan
Yang4, Amelia K. Read7, Seunghee Kim-Schulze8, Jin G. Park1, Marshall Posner9, Melissa A.
Wilson Sayres3,5, Andrew Sikora6, and Karen S. Anderson 1,3
1Biodesign Center for Personalized Diagnostics, 2School of Biological and Health Systems
Engineering, 3School of Life Sciences, 4Biodesign Institute Bioinformatics Core Facility, and
5Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85004, USA;
6Department of Otolaryngology and Head and Neck Surgery, Baylor College of Medicine,
Houston, TX 77030, USA; 7Department of Otolaryngology, Stanford University, Stanford, CA
94305, USA; 8Human Immune Monitoring Center, 9Tisch Cancer institute, Icahn School of
Medicine at Mount Sinai Medical Center, New York, NY, USA
*Current Address: Surgery Branch, National Cancer Institute, Bethesda, MD 20892, USA
Running Title: Immunogenic and dysfunctional CD8+ T-cells in HPV+ HNSCC
Corresponding Author: Karen S. Anderson, The Biodesign Institute, A220E, Center for
Personalized Diagnostics, Arizona State University, Tempe, AZ 85287. Phone: 480-965-6982;
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
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Figure Legends
Fig. 1. HPV16 E2, E6 & E7 epitope distribution and immunogenicity in HPV+ HNSCCs.
(A) Distribution of 59 predicted HPV16-peptides by each HLA-allele ranked from highest to
lowest. (B) Odds ratio of HLA-allele frequency from (A) in HPV+ HNSCC patients (N=77)
compared to HPV- HNSCC patients (N=64) *P = 0.059 (C) Summary of CTL-reactivity.
Predicted HPV16-peptides were pooled according to antigen (Table S1) and tested for CTL-
reactivity by IFNγ Elispot. P-values from Wilcoxon rank-sum test are shown. CEF - Positive
CTL-epitopes pool from CMV, EBV, Flu (D) Representative example of CTL-reactivity from one
HPV+ HNSCC patient PBMC with SFUs after background subtraction (left panel) and images
from each pool in triplicate (right panel). (E) Seroreactivity of HPV16-E2, E6, E7 antigens in
HPV+ HNSCC MSSM patients screened for CTL-responses by Rapid-ELISA (SI Methods) (F)
Seroreactivity and CTL-reactivity concordance for each HPV-antigen in responding HPV+
HNSCC patients. Circles are proportional to the number of responding HPV+ HNSCC patients
for each antigen. % represent patient responses.
Fig. 2. Landscape of CTL-epitopes from HPV16 E2, E6 and E7 in HPV+ HNSCCs. HPV+
HNSCC PBMCs from the initial pooled antigen screen (Fig. 1C), were tested against individual
HPV16-predicted peptides corresponding to the patient HLA-type (SI methods). (A) Summary of
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163
Published OnlineFirst August 28, 2018.Cancer Res Sri Krishna, Peaches Ulrich, Eric Wilson, et al. dysfunction of CD8+ T cells in head and neck cancerHuman papilloma virus specific immunogenicity and
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 28, 2018; DOI: 10.1158/0008-5472.CAN-18-0163