Deciphering the Role of Regulatory CD4 T Cells in Oral and Oropharyngeal Cancer: A Systematic Review

Abstract

Background: Recruiting regulatory CD4 T cells (Tregs) into the tumor microenvironment is an important tumor escape mechanism. Diminishing these suppressive cells is therefore one of the targets of cancer immunotherapy. Selective depletion of Tregs has proven successful in enhancing anti-tumor immunity and therapeutic efficacy in multiple tumor types. However, the role of Tregs in oral/oropharyngeal cancers is unclear with conflicting evidence regarding the effect of these suppressive cells on tumor prognosis. In this study, we sought to review the role of Tregs in oral/oropharyngeal cancer with the aim of deciphering the controversy regarding their effect on tumor progression and prognosis.Methods: A systematic review of the literature pertaining to the role of Tregs in oral/oropharyngeal cancer was performed using Scopus, Embase, and PubMed. Forty-five records were deemed eligible and data describing methodology of Treg detection, tumor type, and association with prognosis were extracted.Results: Of the 45 eligible manuscripts accepted for this systematic review, thirty-nine studies reported data from human subjects while the remaining studies focused on animal models. Sixteen studies were carried out using peripheral blood samples, while samples from the tumor site were analyzed in 18 studies and 11 studies assessed both blood and tumor samples. The transcriptional factor, Foxp3, was the most commonly used marker for Treg identification (38/45). The findings of 25 studies suggested that an increase in Tregs in the tumor microenvironment and/or peripheral blood was associated with poorer prognosis. These conclusions were attributed to the suppression of immune responses and the consequent tumor progression. Conversely, nine studies showed an increase in Tregs in peripheral blood and/or tumor microenvironment was related to a favorable prognosis, particularly in the presence of human papilloma virus (HPV), the status of which was only assessed in 11 studies.Conclusions: This review underlines the importance of host immunity in the behavior of oral/oropharyngeal cancer. Furthermore, we report an apparent lack of clarity regarding the true role Tregs play in oral/oropharyngeal cancer progression which could be attributed to inconsistent detection techniques of Tregs. Our results therefore highlight the need for clearer methodologies and more robust phenotyping when defining Tregs.

Prognostic Potential of Tumor-Infiltrating Immune Cells in Resectable Oral Squamous Cell Carcinoma

“…This might come from the diversity of CD4 + lymphocyte subtypes and their opposing functions. A systematic review on OSCC and OPSCC reported that most studies investigate the subset of regulatory T cells (CD4 + Foxp3 + ) and despite narrowing the range of CD4 + cell types, the results are still contradictory, with a third of the studies associating an increased regulatory T cell infiltration with a poor prognosis, while the other two-thirds reporting improved outcomes in these patients [ 40 ]. In our study, we found a significantly higher infiltration with CD4 + cells at the front of invasion compared to the intratumor compartment.…”

Serum Levels of OX40 in Early and Late-Stage Oral Squamous Cell Carcinoma

“…The current trial of OX40 agonist demonstrated an increase in TILs and improvement in the patients with an adequate safety profile [ 22 ]. However, the effect of immune checkpoint blockade therapy on OSCC is limited and the subtypes within the TILs and expression of immune cell subtypes should be also taken into account [ 23 ].…”

Immune Conversion of Tumor Microenvironment by Oncolytic Viruses: The Protoparvovirus H-1PV Case Study

“…These cytokines induce apoptosis of tumor cells and/or activation of anticancer immune responses (16). CD4 + T helper cells also contribute to the cytotoxic anticancer immune response mediated by CTLs, by stimulating CTL priming through the release of cytokines, particularly IFN-γ (17).…”