PD-1-expressing B cells suppress CD4+ and CD8+ T cells via PD-1/PD-L1-dependent pathway
Introduction
Based on the etiological and clinical features, thyroid cancers can be distinguished into differentiated thyroid cancer (DTC) and anaplastic thyroid cancer (ATC) (Carling and Udelsman, 2014). DTC is a slow-progressing disease and when diagnosed early, DTC can be effectively managed with surgical resection and radioiodine therapy (131I), with a five-year survival rate near 100%. However, at later stages, DTC has a significantly worse five-year survival rate at approximately 30% to 80% (Carhill et al., 2015; Durante et al., 2006). Distant metastasis is found in a small minority of patients, and a high proportion of these patients eventually succumbs to secondary malignancies (Mazzaferri and Jhiang, 1994). Also, the malignancy can recur in patients who initially responded to treatment (Mazzaferri and Massoll, 2002). The other thyroid cancer subtype ATC, though rare, is one of the most aggressive human malignancies. ATC tumors often invade or encase vital body structures in the patients, making complete resection unachievable (McIver et al., 2001). Response to other treatments is also poor. Patients with ATC have a median survival of less than five months. In addition, it is thought that ATC can arise from well-differentiated tumors (Carling and Udelsman, 2014). Further research into the genetic, environmental, and immunological factors involved in thyroid cancer is needed for the development of better therapeutic strategies.
We previously demonstrated that IL-10-producing B cells were enriched in DTC patients [manuscript under review]. These B cells belong to a broader category of regulatory B (Breg) cells that have the capacity to inhibit pathogenic inflammation and promote peripheral tolerance, mainly through the production of IL-10 (Rosser and Mauri, 2015; Tedder and Leonard, 2014; Xiao et al., 2012). Recently, it is shown that B cells can also regulate immune responses via the PD-1/PD-L1 pathway (Gallego-Valle et al., 2018; Khan et al., 2015; Siewe et al., 2013; Xiao et al., 2016). Activation of B cells via CpG alone or a combination of toll-like receptor agonists, together with CD40 costimulation, could significantly increase the expression of both PD-1 and PD-L1 on those B cells (Gallego-Valle et al., 2018; Siewe et al., 2013). Via PD-L1, Breg cells could reduce the expansion of PD-1+ Tfh cells, thus downregulating humoral immune responses (Khan et al., 2015). Adoptive transfer of PD-L1hi B cells attenuated murine experimental autoimmune encephalomyelitis. In murine EMT-6 model, tumor-infiltrating B cells demonstrated higher PD-L1 expression than splenic B cells (Zhang et al., 2016). These B cells could suppress the proliferation of CD4+ T cells and CD8+ T cells in a manner reversible by anti-PD-L1 antibody. In advanced hepatocellular carcinoma, PD-1hi B cells comprised approximately 10% of total B cells, and upon encountering PD-L1, these PD-1hi B cells, suppressed the response of tumor-specific T cells, and enhanced tumor growth via IL-10 (Xiao et al., 2016).
In DTC, whether B cells could modulate antitumor immunity via the PD-1/PD-L1 pathway has not been demonstrated. Here, we approached this problem by identifying the existence and level of PD-1/PD-L1 expression in B cells from DTC patients. Later, whether these B cells affected the function of autologous T cells was investigated. Finally, effect of treatment on the frequency of PD-1+ B cells was examined.
Section snippets
Study subjects
This study was approved by the Ethics Committee of The Affiliated Hospital of Qingdao University. Prior to the collection of samples, all volunteers gave written informed consent for participation in this study. Diagnosis and recruitment were performed at The Affiliated Hospital of Qingdao University. To qualify for this study, the patients must be between 18 to 65 years of age, and present new onset untreated DTC. Controls were recruited from age- and sex-matched healthy individuals. In
PD-1/PD-L1 expression B cells from DTC patients and controls
To examine the expression of PD-1/PD-L1 on B cells and the role of PD-1/PD-L1-expressing B cells in DTC pathogenesis, we collected the peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 20) and the PBMCs from DTC patients (n = 20). Characteristics of study participants are presented in Table 1. In addition, tumor-infiltrating lymphocytes (TILs) from the stage II and stage III DTC patients (n = 12) were obtained from resected tumors obtained after thyroidectomy. The patients
Discussion
In this study, we characterized PD-1-expressing B cells in DTC patients and healthy controls. These PD-1+ B cells expressed high PD-L1, and could be induced upon long-term, but not short-term, anti-Ig/CD40 L stimulation. However, even after long-term stimulation, the PD-1+ B cell frequency was still low at 3%–4%. in vitro incubation with autologous T cells demonstrated that these PD-1+ B cells could suppress the expansion of T cells and reduce their viability, thus suggesting that these PD-1+ B
Conflict of interest
None.
References (21)
- et al.
CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients
Immunity
(2010) - et al.
Anaplastic thyroid carcinoma: a 50-year experience at a single institution
Surgery
(2001) - et al.
Regulatory B cells: origin, phenotype, and function
Immunity
(2015) - et al.
Long-term outcomes following therapy in differentiated thyroid carcinoma: NTCTCS registry analysis 1987-2012
J. Clin. Endocrinol. Metab.
(2015) - et al.
Thyroid Cancer
Annu. Rev. Med.
(2014) - et al.
Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells
J. Immunol.
(2011) - et al.
Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy
J. Clin. Endocrinol. Metab.
(2006) - et al.
Generation of human breg-like phenotype with regulatory function in vitro with bacteria-derived oligodeoxynucleotides
Int. J. Mol. Sci.
(2018) - et al.
PD-1 and its ligands in tolerance and immunity
Annu. Rev. Immunol.
(2008) - et al.
PD-L1hi B cells are critical regulators of humoral immunity
Nat. Commun.
(2015)
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