Tbet-positive regulatory T cells accumulate in oropharyngeal cancers with ongoing tumor-specific type 1\u2009T cell responses

S J Santegoets,J J Van Ham,S H Van Der Burg,M J P Welters,E S Jordanova,I Ehsan,S L Van Egmond,C L Duurland

doi:10.1186/s40425-019-0497-0

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 Foxp3hi 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–Foxp3hi Tregs and their Tbethi 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.

Highlights

Foxp3+ regulatory T cells (Tregs) are pivotal in suppressing pathological and physiological immune responses [1]
High numbers of Foxp3+Tbet+ Treg cells are found in the oropharyngeal squamous cell carcinoma (OPSCC) microenvironment To assess the number of conventional and Tbet-expressing Foxp3+ Tregs in cancer patients, we analyzed 41 primary OPSCC tumors by three-color immunofluorescent confocal microscopy
In mice, Foxp3+Tbet+ Tregs were shown to play a role in suppressing Th1-like effector T cell responses [14, 15]

Summary

Introduction

Foxp3+ regulatory T cells (Tregs) are pivotal in suppressing pathological and physiological immune responses [1]. Tregs are generally considered to suppress the local tumor immune response. Different types of impact have been reported for Tregs in patients suffering from head and neck cancer, including oropharyngeal squamous cell carcinoma (OPSCC) [2]. Some studies suggested a negative prognostic value for high frequencies of tumor-infiltrating CD4+CD25 +Foxp3+ Tregs in head and neck cancer [3,4,5], whereas others demonstrated a non-predictive [6] or even positive prognostic role [7,8,9,10] for these cells. Recent studies have shown that Tregs can adopt different transcriptional profiles allowing them to regulate specific types of effector T cells [11]. Foxp3+Tbet+ Tregs are phenotypically stable [15] and regulate Th1 inflammatory sites in vivo, thereby counterbalancing unwanted tissue destruction and immunopathology [14]

Methods

Results

Conclusion