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