Tbet-positive regulatory T cells accumulate in oropharyngeal cancers with ongoing tumor-specific type 1 T cell responses

S J Santegoets; C L Duurland; E S Jordanova; J J van Ham; I Ehsan; S L van Egmond; M J P Welters; S H van der Burg

doi:10.1186/s40425-019-0497-0

Tbet-positive regulatory T cells accumulate in oropharyngeal cancers with ongoing tumor-specific type 1 T cell responses

J Immunother Cancer. 2019 Jan 18;7(1):14. doi: 10.1186/s40425-019-0497-0.

Authors

S J Santegoets¹, C L Duurland¹, E S Jordanova², J J van Ham¹, I Ehsan¹, S L van Egmond³, M J P Welters¹, S H van der Burg⁴

Affiliations

¹ Departments of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands.
² Department of Obstetrics and Gynecology, Center for Gynecological Oncology Amsterdam (CGOA) Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
³ Departments of Otorhinolaryngology and Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands.
⁴ Departments of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands. shvdburg@lumc.nl.

Abstract

Regulatory T cells (Tregs) may comprise different subsets allowing them to efficiently suppress different types of effector T cells. In this study, we show that high numbers of both conventional and Tbet co-expressing Foxp3^hi Tregs accumulate in human papilloma virus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC). The infiltration of Tbet+ Foxp3+ Tregs was strongly correlated with a concomitant tumor-specific and conventional type 1-oriented intratumoral T cell infiltrate. Both conventional CD4+CD25+CD127-Foxp3^hi Tregs and their Tbet^hi counterparts exhibited an activated phenotype, co-expressed high levels of CTLA4 and Helios and exhibited a maximally demethylated Foxp3 gene locus TSDR, indicating their full capacity to impede a type 1 effector T cell response. Interestingly, while the prognostic value of conventional Tregs was neutral, a high intratumoral frequency of Tbet+ Tregs was associated with prolonged disease-specific survival, most likely because their presence reflected high numbers of effector T cells. The presence of these Tbet+ Tregs may in part explain why a dense type 1-oriented immune infiltrate in OPSCC is not enough to fully control tumor growth.

Keywords: Foxp3; HPV; Head and neck cancer; Tumor microenvironment; Type 1 immunity.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Female
Forkhead Transcription Factors / immunology
Humans
Lymphocytes, Tumor-Infiltrating / immunology*
Male
Middle Aged
Oropharyngeal Neoplasms / etiology
Oropharyngeal Neoplasms / immunology*
Papillomavirus Infections / complications
Papillomavirus Infections / immunology*
T-Box Domain Proteins / immunology*
T-Lymphocytes, Regulatory / immunology*
Uterine Cervical Neoplasms / etiology
Uterine Cervical Neoplasms / immunology

Substances

FOXP3 protein, human
Forkhead Transcription Factors
T-Box Domain Proteins
T-box transcription factor TBX21