Abstract
Human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) and transmembrane and immunoglobulin domain containing 2 (TMIGD2) are new immune checkpoint molecules of the B7:CD28 family; however, little research has been performed on these immune checkpoint molecules. In this study, we used oral squamous cells carcinoma (OSCC) tissue microarrays and immunohistochemistry methods to investigate the expression patterns of HHLA2 and TMIGD2 in OSCC. After comparing the HHLA2 and TMIGD2 expression levels in OSCC, dysplasia, and mucosa, we found increased HHLA2 expression in OSCC and dysplasia, while the TMIGD2 expression was decreased in OSCC and dysplasia. Using the Kaplan-Meier method and log-rank test, we found that higher HHLA2 or TMIGD2 expression levels in OSCC indicate poor prognosis. Furthermore, two-tailed Pearson's statistical analysis revealed that the HHLA2 expression levels in OSCC, dysplasia, and mucosa were positively correlated with the T cell immunoglobulin and mucin-domain containing-3 (TIM3), lymphocyte-activation gene 3 (LAG3), B7 homolog 3 protein (B7-H3), B7 homolog 4 protein (B7H4), and V-domain Ig suppressor of T cell activation (VISTA) levels, while the TMIGD2 expression levels in OSCC, dysplasia, and mucosa were inversely correlated with the TIM3, LAG3, and B7H3 levels. Our current study demonstrates that HHLA2 may serve as an immune target for OSCC therapy and that the TMIGD2 expression level in OSCC could forecast patient prognosis.
Highlights
B7:CD28 family pathways have key roles in orchestrating T cell activation and tolerance and are promising therapeutic targets [1]
transmembrane and immunoglobulin domain containing 2 (TMIGD2) is a HHLA2 receptor [5], and it is expressed by all naive T cells, the majority of natural killer (NK) cells and half of the memory T cells, it is not expressed by T regulatory cells or B cells [5]; TMIGD2 expression is lost in activated T cells [6]
HHLA2 Levels Are Increased in oral squamous cells carcinoma (OSCC) and Dysplasia, while TMIGD2 Levels Are Decreased in OSCC and Dysplasia, and Both Cases Indicate Poor Prognosis
Summary
B7:CD28 family pathways have key roles in orchestrating T cell activation and tolerance and are promising therapeutic targets [1]. HHLA2 shares significant homology with the B7 family [4] and has been demonstrated to have both stimulatory and inhibitory properties on T cells [5]. TMIGD2 is a HHLA2 receptor [5], and it is expressed by all naive T cells, the majority of natural killer (NK) cells and half of the memory T cells, it is not expressed by T regulatory cells or B cells [5]; TMIGD2 expression is lost in activated T cells [6]. The HHLA2/TMIGD2 interaction selectively costimulates human T cell growth and cytokine production via an AKT-dependent signaling cascade [6]. HHLA2 and TMIGD2 are both absent in mouse and rat [7, 8]
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