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. 2016 Sep;65(9):1035-45.
doi: 10.1007/s00262-016-1867-9. Epub 2016 Jul 6.

B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma

Lei Wu  1 , Wei-Wei Deng  1 , Guang-Tao Yu  1 , Liang Mao  1 , Lin-Lin Bu  1 , Si-Rui Ma  1 , Bing Liu  1   2 , Wen-Feng Zhang  1   2 , Zhi-Jun Sun  3   4
Affiliations

B7-H4 expression indicates poor prognosis of oral squamous cell carcinoma

Lei Wu et al. Cancer Immunol Immunother. 2016 Sep.

Abstract

Checkpoint blockade therapy utilizing monoclonal antibodies to reactivate T cells and recover their antitumor activity makes an epoch in cancer immunotherapy. The role of B7-H4, a novel negative immune checkpoint, in oral squamous cell carcinoma (OSCC) has still not been elucidated. In this study, tissue samples from human OSCC, which contains 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa specimens, and Tgfbr1/Pten 2cKO mice OSCC model were stained with B7-H4 antibody to analyze the correlations between B7-H4 expression and clinicopathological characteristics. Kaplan-Meier analysis was used to compare the survival of patients with high B7-H4 expression and patients with low B7-H4 expression. We found B7-H4 is highly expressed in human OSCC tissue, and the B7-H4 expression level was associated with the clinicopathological parameters containing pathological grade and lymph node status. Moreover, we confirmed that B7-H4 was overexpressed in Tgfbr1/Pten 2cKO mice OSCC model. Our data also indicated that patients with high B7-H4 expression had poor overall survival compared with those with low B7-H4 expression. Furthermore, this study demonstrated that B7-H4 was positively associated with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236). Taken together, these findings suggest B7-H4 is a potential _target in the treatment of OSCC.

Keywords: B7-H4; Immune checkpoint; Immunotherapy; Oral squamous cell carcinoma; Tissue microarray; Transgenic mice.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
High expression of B7-H4 in oral squamous cell carcinoma. a Representative hematoxylin-eosin (HE, left) and immunohistochemistry staining (right) of B7-H4 in oral mucosa and in primary OSCC tissue. Scale bar 50 μm. b Quantification of immunohistochemical histoscore of B7-H4 among oral mucosa (n = 43), dysplasia (Dys, n = 48) and primary oral squamous cell carcinoma (OSCC, n = 165) (all data are presented as mean ± SEM, one-way ANOVA with post Tukey test. ***P < 0.001). c Kaplan–Meier curve showing head neck squamous cell carcinoma patient with low B7-H4 expression (n = 82) survival longer than B7-H4 high expression patient, which log-Rank analysis reveal the difference was significant (n = 82, P < 0.05)
Fig. 2
Fig. 2
Human OSCC tissue array analysis revealed that B7-H4 correlated with high-grade OSCC. a Representative hematoxylin-eosin staining (HE, left) and immunohistochemical staining (right) of B7-H4 in human oral cancer tissues with different grades (I–III) (Scale bars 50 μm). b Quantitative analysis of histoscore of B7-H4 expression in grade I, grade II and grade III. B7-H4 levels in high-grade OSCC were significantly higher when compared with low-grade OSCC (one-way ANOVA with post Tukey test, P < 0.01). c The expression of B7-H4 was correlated with lymph node status of human OSCC (t test, P < 0.05). *P < 0.05; **P < 0.01. Scale bars 50 μm
Fig. 3
Fig. 3
Increased expression of B7-H4 in OSCC with pre-operation cisplatin based chemotherapy. a Representative HE staining (left) and immunohistochemical staining (right) of OSCC with pre-operation inductive TPF (cisplatin, docetaxel, and fluorouracil) chemotherapy. b Representative HE staining (left) and immunohistochemical (right) staining of primary OSCC and metastasis lymph node (LN). c Quantitative of immunohistochemistry staining using digital scanner and histoscore of B7-H4 expression with pre-operation inductive TPF was significantly higher than primary OSCC (t test, P < 0.05). d There was no significant difference between the expression level of B7-H4 in primary OSCC and metastasis lymph node (t test, P > 0.05). e There was no significant difference between the expression level of B7-H4 in primary OSCC and OSCC with pre-operation radiotherapy treatment (RT) (t test, P > 0.05). f There was no significant difference between the expression level of B7-H4 in primary OSCC and recurrence (t test, P > 0.05). Scale bars 50 μm
Fig. 4
Fig. 4
Correlation of B7H4 with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236) in human OSCC tissue microarray. a Representative immunohistochemical staining of PD-L1, CD11b, CD33, PI3Kα p110 and p-S6 (S235/236) in human oral cancer tissue (right) compared with normal oral mucosa (left) (Scale bars 50 μm). b Hierarchical clustering presents the protein expression correlation of PD-L1, CD11b, CD33, PI3K, and p-S6 in human OSCC tissue microarray
Fig. 5
Fig. 5
Quantification and correlation of B7-H4 with PD-L1, CD11b, CD33, PI3Kα p110 and p-S6 (S235/236) in human OSCC tissue. Correlation of B7-H4 with PD-L1 (a), CD11b (b), CD33 (c), PI3Kα p110 (d), and p-S6(S235/236) (e) in human OSCC tissue array
Fig. 6
Fig. 6
High expression of B7-H4 in Tgfbr1/Pten 2cKO mice OSCC and Correlation of PD-L1, CD11b, PI3Kα p110 and p-S6 (S235/236) in mice OSCC tissue. a Immunohistochemistry of B7-H4, PD-L1, CD11b, PI3Kα p110, and p-S6(S235/236) in tongue of the wild-type (WT) mice and the tumor of Pten/Tgfbr1 conditional knock out mice (Scale bar 25 µm). b Correlation of B7-H4 with PD-L1, CD11b, PI3Kα p110 and p-S6 (S235/236) in mice OSCC tissue
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