Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis

Objectives: Compared with non-smoking counterparts, smoking-associated lung cancers have a higher mutational load, resulting in the creation of more tumor neoantigens and increased immunogenicity. B7-H3 (also known as CD276) belongs to a family of immune modulators that includes PD-1 and PD-L1 (also known as B7-H1 or CD274). Considering the evidence that PD-L1 inhibitors have been shown to be more effective against lung cancer in smokers, we herein examined the prognostic interaction of tumor B7-H3 expression level with smoking history in lung adenocarcinoma patients. Materials and methods: Using tissue microarrays comprising 270 consecutive cases of lung adenocarcinoma, we evaluated tumor B7-H3 expression by immunohistochemistry. We examined the prognostic association between B7-H3 expression levels and smoking history, using Cox proportional hazards regression analysis and the log-rank test. Additionally, we used logistic regression analysis to examine the correlations between B7-H3 expression levels and clinicopathological/molecular features of lung adenocarcinoma. Results: The association of B7-H3 expression with survival differed by smoking history (P-interaction = 0.014); high B7-H3 expression was associated with decreased lung cancer-specific survival in moderate/heavysmoking patients (smoking index [SI] >= 400) (hazard ratio [HR] = 3.07, 95% confidence interval [CI] = 1.74-5.49, P=0.0001; log-rank: P <0.0001), but not in non/light-smoking patients (SI < 400) (HR=1.14, 95% CI = 0.63-1.96, P=0.64; log-rank: P=0.64). Interestingly, in moderate/heavy-smoking patients, high B7-H3 expression was associated with decreased survival in stage I cancer (log-rank; P=0.0005), whereas it showed no significant difference of survival in stage II-IV cancer (P=0.37). High B7-H3 expression was associated with smokers (univariable odds ratio [OR] = 2.63, 95% CI = 1.51-4.65; P=0.0005) and independently associated with EGFR wild-type status (multivariable OR = 2.80, 95% CI =1.38-5.84; P=0.0042). Conclusions: We demonstrated that the prognostic association of B7-H3 expression indeed differed according to smoking history. Our study also showed the significant association of high B7-H3 expression with EGFR wild-type and smoking patients, indicating the potential effectiveness of anti-B7-H3 therapy for EGFR wild-type or smokers' lung adenocarcinoma. (C) 2016 Published by Elsevier Ireland Ltd.