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. 2017 Sep 1;23(17):5202-5209.
doi: 10.1158/1078-0432.CCR-16-3107. Epub 2017 May 24.

B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

Mehmet Altan  1   2 , Vasiliki Pelekanou  3 , Kurt A Schalper  1   3 , Maria Toki  3 , Patricia Gaule  3 , Konstantinos Syrigos  4 , Roy S Herbst  1 , David L Rimm  5   3
Affiliations

B7-H3 Expression in NSCLC and Its Association with B7-H4, PD-L1 and Tumor-Infiltrating Lymphocytes

Mehmet Altan et al. Clin Cancer Res. .

Abstract

Purpose: The immune checkpoint PD-1 and its receptor B7-H1 (PD-L1) are successful therapeutic targets in cancer but less is known about other B7 family members. Here, we determined the expression level of B7-H3 protein in non-small cell lung cancer (NSCLC) and evaluated its association with tumor-infiltrating lymphocytes (TIL), PD-L1, B7-H4, and major clinicopathologic characteristics is in 3 NSCLC cohorts.Experimental design: We used multiplexed automated quantitative immunofluorescence (QIF) to assess the levels of B7-H3, PD-L1, B7-H4, and TILs in 634 NSCLC cases with validated antibodies. Associations between the marker levels, major clinicopathologic variables and survival were analyzed.Results: Expression of B7-H3 protein was found in 80.4% (510/634) of the cases. High B7-H3 protein level (top 10 percentile) was associated with poor overall survival (P < 0.05). Elevated B7-H3 was consistently associated with smoking history across the 3 cohorts, but not with sex, age, clinical stage, and histology. Coexpression of B7-H3 and PD-L1 was found in 17.6% of the cases (112/634) and with B7-H4 in 10% (63/634). B7-H4 and PD-L1 were simultaneously detected only in 1.8% of NSCLCs (12/634). The expression of B7-H3 was not associated with the levels of CD3-, CD8-, and CD20-positive TILs.Conclusions: B7-H3 protein is expressed in the majority of NSCLCs and is associated with smoking history. High levels of B7-H3 protein have a negative prognostic impact in lung carcinomas. Coexpression of B7-H3 with PD-L1 and B7-H4 is relatively low, suggesting a nonredundant biological role of these targets. Clin Cancer Res; 23(17); 5202-9. ©2017 AACR.

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Conflict of interest statement

Relevant Conflicts of Interest: Dr. Rimm has served as a consultant/advisor for Astra Zeneca, Bristol Meyers Squib, Cell Signaling Technology, Ultivue, and Perkin Elmer and has received grant support from Genoptix and Gilead Sciences

Figures

Figure 1
Figure 1
A) QIF score distribution of tumor B7-H3 protein expression in Cohort B. Scores are expressed as arbitrary units of fluorescence and the dashed red line indicates the signal detection threshold determined by visual cut off as described in the methods; A1 and A2 are examples of TMA spots with negative and positive B7-H3 signal respectively (DAPI in blue, Cytokeratin mask in green (Cy3 channel) and B7-H3 is in red (Cy5 channel), Figure 1B and 1C display QIF score distribution of tumor B7-H3 in Cohort A and C, respectively.
Figure 2
Figure 2
Kaplan Meier overall survival curve in 3 cohorts; Figure A, B and C are showing tumor B7-H3 QIF positive and negative cases (red: positive and green: negative) in Cohort A, B and C respectively. Figure D, E and F are showing highest 10% QIF B7-H3 QIF score as a cut off in Cohort A, B and C respectively (red: B7-H3 protein expression highest 10%, green: B7-H3 protein expression lowest or negative 90%).
Figure 3
Figure 3
A-C QIF score regressions of markers the dashed red line indicates the signal detection threshold determined by visual cut off. A) QIF score regressions for co-expression rates of tumor PD-L1 and B7-H3 protein, B) QIF score regressions for co-expression rates of tumor B7-H3 and B7-H4 protein, C) QIF score regressions for co-expression rates of tumor PD-L1 and B7-H4 protein.
Figure 4
Figure 4
Detection of B7-H3 and B7-H4 protein expression to assess co-localization using immunofluorescence (QIF) in lung cancer. A) Representative fluorescence images showing the simultaneous detection of B7-H3 (red channel), B7-H4 (blue channel) and cytokeratin (green channel, inserted box is highlighting the area that has been magnified in figure 2 C–F. B) Simultaneous detection of B7-H3 (red channel), B7-H4 (blue channel) C) 4′,6-diamidino-2-phenylindole (DAPI) only in purple channel, D) Cytokeratin only in green channel, E) B7-H3 only in red channel, D) B7-H4 only in blue channel. Bar=100 μm.
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