APOBEC mutagenesis is tightly linked to the immune landscape and immunotherapy biomarkers in head and neck squamous cell carcinoma Journal Article

Authors: Faden, D. L.; Ding, F.; Lin, Y.; Zhai, S.; Kuo, F.; Chan, T. A.; Morris, L. G.; Ferris, R. L.
Article Title: APOBEC mutagenesis is tightly linked to the immune landscape and immunotherapy biomarkers in head and neck squamous cell carcinoma
Abstract: HNSCC is an immunologically active tumor with high levels of immune cell infiltration, high mutational burden and a subset of patients who respond to immunotherapy. One of the primary sources of mutations in HNSCC is the cytidine deaminase APOBEC3, which is a known participant in innate immunity. Why particular HNSCCs have higher rates of APOBEC mutations and how these mutations relate to the immune microenvironment remains unknown. Utilizing whole exome and RNA-Seq datasets from TCGA HNSCCs we annotated APOBEC mutations, immune cell populations, activating and end effectors of immunity and neoantigens in order to interrogate the relationship between APOBEC mutations and the immune landscape. Immune cell populations and composite scores of immune activation were tightly associated with APOBEC mutational burden (p = 0.04–1.17e-5). HNSCC had the highest levels of IFNy across cancer types with high APOBEC mutational burden, with the highest IFNy scores in HPV mediated HNSCC. Tumor specific neoantigens were significantly correlated with APOBEC mutational burden while other sources of neoantigens were not (0.53 [0.24, 0.76] p = 8e-5). The presence of a germline APOBEC polymorphism was more prevalent in non-white, non-black patients and within this group, patients with the polymorphism had higher APOBEC mutational burden (p = 0.002). APOBEC mutations are tightly linked to immune activation and infiltration in HNSCC. Multiple mechanisms may exist within HNSCC leading to APOBEC mutations including immune upregulation in response to neoantigens and viral infection, via induction of IFNy. These mechanisms may be additive and not mutually exclusive, which could explain higher levels of APOBEC mutations in HPV mediated HNSCC. © 2019 Elsevier Ltd
Keywords: immunotherapy; head and neck cancer; immune microenvironment; mutational signatures; apobec
Journal Title: Oral Oncology
Volume: 96
ISSN: 1368-8375
Publisher: Elsevier Inc.  
Date Published: 2019-09-01
Start Page: 140
End Page: 147
Language: English
DOI: 10.1016/j.oraloncology.2019.07.020
PROVIDER: scopus
PUBMED: 31422205
Notes: Article -- Export Date: 4 September 2019 -- Source: Scopus
Citation Impact
MSK Authors
  1. Timothy Chan
    280 Chan
  2. Luc Morris
    167 Morris
  3. Fengshen Kuo
    28 Kuo