Patterns of antibody responses to nonviral cancer antigens in head and neck squamous cell carcinoma patients differ by human papillomavirus status.

Dominik S Gangkofner,Dana Holzinger,Gerhard Dyckhoff,Patrick J Schuler,Martina A Broglie,Julia Butt,Hans A Kestler,Gunnar Wichmann,Johann M Kraus,Andreas Dietz,Stefan B Eichmüller,Lea Schroeder,Cornelia Brunner,Paolo Boscolo‐Rizzo,Inka Zörnig,Johannes Doescher,Gunnar Völkel,Dirk Jäger,Tim Waterboer,Michael Pawlita,Peter Möller,Simon Laban,Mn Theodoraki ,Thomas Hoffmann ,Marlene C Wigand ,Ralf Marienfeld ,Jasmin Ezić ,Christel Herold‐Mende

doi:10.1002/ijc.32623

Abstract

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in almost 900,000 cases annually resulting in approximately 450,000 cancer deaths per year.[1]
There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC)
Multiobjective optimization may be key to develop tailored antigen panels to improve the performance of multiplex serology to cancer antigens as a liquid biopsy of the cancer-antigen repertoire in the tumor

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is diagnosed in almost 900,000 cases annually resulting in approximately 450,000 cancer deaths per year.[1]. Shared cancer antigens include germline antigens such as cancer-testis antigens that are exclusively expressed in tumor tissue and germline cells[5,6] or cancer-retina antigens,[7] oncogenes or mutated tumor-suppressor genes overexpressed in cancer tissue such as p538 and foreign antigens such as viral antigens.[9] The expression of cancer antigens can be determined by RNA or protein detection in tissue biopsies. Such analyses are expensive, availability of tissue may be limited and an invasive procedure is needed to obtain such biopsies. Antibody responses (AR) to viral antigens have previously been used to identify HPV-positive patients,[10,11,12] AR to shared, nonviral antigens may play an important role for immunotherapy of HPV-positive and HPV-negative HNSCC.[13,14]

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Methods

Results

Conclusion