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

Abstract 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/heavy-smoking patients (smoking index [SI]≥400) (hazard ratio [HR]=3.07, 95% confidence interval [CI]=1.74–5.49, P =0.0001; log-rank: P 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.