title: Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis.
abstract: 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.
  
  
  
  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.
  
  
  
  The association of B7-H3 expression with survival differed by smoking history (Pinteraction=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<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).
  
  
  
  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.
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inamura
authors.affiliation: Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yokouchi
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; Department of Integrated Pulmonology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Sakakibara
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Ninomiya
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Sophia
authors.initials: S
authors.lastname: Subat
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagano
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Nomura
authors.affiliation: Thoracic Oncology Center, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Translational Medicine & Clinical Pharmacology Department, Daiichi Sankyo Co. Ltd., 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-0005, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Shibutani
authors.affiliation: Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Electronic address: ishikawa@jfcr.or.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
keywords: B7-H3; Immune checkpoint; Immunotherapy; Lung cancer; Prognostic interaction; Smoking