Discussion
There was little study investigating the PD-L2 expression in thymoma. And PD-L2 was less well studied. Human PD-L2 are expressed on dendritic cells and medullary thymic epithelial cells [10]. High PD-L2 expression may promote tumor metastasis and predict unfavorable prognosis in solid cancer patients after surgery[13]. Previous studies showed that PD-L2 exerts its main physiological and pathological function in immune tolerance via dampening and modulating T helper type 2 (Th2) response[14]. MG is an autoimmune disease associated with thymus pathologies. A preliminary investigation between the PD-L2 expression in thymoma and MG was shown in the results above.
In this study, the PD-L2 expression was positive in 41 patients (58.6%). However, Isabelle Rouquette et al found that PD-L2 antibody stained no thymic epithelial tumors [15]. Different antibody and cut-off values vary among studies. The positive expression of PD-L2 was associated with B2/B3 histologic type. Because there were few studies put attention in PD-L2 and thymoma, we referred PD-L1 expression. Numerous studies investigating the PD-L1 expression in thymoma indicated that a high expression of PD-L1 was significantly associated with B2/B3 histologic type [16,17]. Most studies played attention to the PD-L1/2 expression with prognosis. A meta-analysis showed high PD-L2 expression might predict unfavorable prognosis. We did not explore the prognosis in these patients but focus in the PD-L2 expression and MG.
Patients with B2 histologic type was the most in this study (44.3%). And the status of MG was associated with B2/B3 histologic types in this study. L. Maggi et al found that AB and B2 thymomas were most frequently observed histologic types in patients with MG[18]. Ströbel, P et al also observed that B2 was the most frequently [19]. However, other authors reported B1 and B2 histologic types as prevalent[20,21]. The positive expression of PD-L2 was also associated with a smaller tumor size. What’s more, the tumor size was smaller in the patients with MG in this study. This can be explained by earlier diagnosis because of the status of MG[22]. The PD-L2 expression was associated with ectopic thymus in this study. The exist of ectopic thymus may play an important role in the pathogenesis of MG in patients with thymoma because of the TFH cells [6]. Furthermore, our group found that ectopic thymus was a poor prognosis factor in patients with MG [23]. Not only the Chi square test showed the positive relationship between PD-L2 expression and MG, but also the logistic regression demonstrated a significantly association between PD-L2 expression and MG in the patients with thymoma. Although age was associated with PD-L2 expression with the multivariate logistic regression analysis in the overall patients, but no significantly association was observed in patients with MG. Therefore, we do have sufficient reason to guess that the PD-L2 expression plays a crucial role in the pathogenesis of MG in patients with thymoma.
In this study, a status of MG in these patients with thymoma was associated with B2/B3 histologic types, but has no significantly associated with gender or Masaoka-Koga stage. There was tendency toward younger age in patients with MG (p=0.052). Kondo K et al found that a female dominance in their patients with thymoma and the patients with MG were significantly younger than those without MG[22]. While Jianfei Shen suggested that MG, WHO histology and Masaoka-Koga stage interrelate with one another. The inter-relationship drawn from their study was that MG was associated with early clinical stage and WHO histology of AB, B1 and B2-type thymomas [24]. The PD-L2 scores was much higher in the patients with MG than without MG (124.1 vs 23.3, p<0.001). We did an analysis of PD-L2 scores in patients with MG only. We found that there were no significantly difference in PD-L2 scores regarding MGFA stage, Masaoka-Koga stage, tumor size or ectopic thymus, but a tendency toward high PD-L2 scores in patients with B2/B3 types.
The different proportion of T-lymphocytes differing in WHO histologic types may contribute the different prevalence of MG. It is speculated that T-lymphocytes development is involved in the pathogenesis of MG in patients with thymoma [25]. And thymomas with MG are enriched for autoreactive T cells with specificity for AChR. And the export of autoreactive CD4+ T cells is of pathogenic relevance of MG[26]. These exporting T cells may carry special signal in the pathogenesis of MG. And there was a positive association between the percentage of CD4+ T cells and MG severity [4]. Furthermore, PD-1 is highly expressed in TFH, the PD-1 signaling involved decreased GC death and increase TFH cytokine production. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cell. [5] Our guess about thymoma related MG pathogenesis is that the PD-L2 co-stimulate PD-1 signal through exporting autoreactive T cells to help germinal center (GC) formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. Furthermore, we will explore the potential mechanism of PD-L2 signal path in thymoma related MG pathogenesis with the techniques of immunofluorescence and flow cytometry.
However, several limitations associated with present study also warrant mention. First, the number of patients was small. Second, this was a retrospective analysis performed at a single institution. Third, we did not investigate the PD-L2 expression with survive.
In conclusions, a strong expression of PD-L2 in thymoma was significantly associated with thymomatous MG and WHO histologic type B2 and B3. On the basis of our results and analysis, PD-L2 may play a potential role in the pathogenesis of thymomatous MG.
There is no conflict of interest in whichever form at the submission of this manuscript